DDX27 in cancer: molecular mechanisms, clinical implications, and therapeutic potential

Abstract

Background

DDX27, a member of the DEAD-box RNA helicase family, plays a pivotal role in RNA metabolism and is essential for diverse cellular processes, including transcription, pre-mRNA splicing, translation, and ribosome biogenesis. Recent findings have implicated DDX27 as a substantial contributor to tumorigenesis and cancer progression across various malignancies, establishing its significance as a molecular hub that interacts with key oncogenic partners such as major vault protein (MVP) and nucleophosmin 1 (NPM1).

Methods

We conducted systematic search in the following comprehensive academic databases: PubMed, MEDLINE or Web of Science. The keywords such as DDX27, DEAD-box protein 27, RNA helicase DDX27 and cancer, tumor or carcinoma were used for searching. This review consolidates the existing literature on DDX27, examining its structural features and biological functions within the context of tumorigenesis. We systematically explore the molecular mechanisms by which DDX27 influences tumor development and progression, focusing particularly on its roles across different cancer types, including colorectal cancer (CRC), gastric cancer (GC), breast cancer (BC), hepatocellular carcinoma (HCC), and oral squamous cell carcinoma (OSCC). Key molecular mechanisms such as NF-κB activation and ERK1/2 phosphorylation involved in DDX27-related pathways are discussed.

Results

Our comprehensive summary elucidates the context-dependent roles of DDX27 across various cancers, highlighting its associations with advanced disease stages, metastasis, and therapeutic resistance. We also assess the potential of DDX27 as a diagnostic and prognostic biomarker, correlating its expression levels with negative clinical outcomes.

Conclusion

Novel therapeutic strategies targeting DDX27 are proposed, including RNA interference techniques (siRNA and shRNA), miRNA-based therapies (miR-617 mimics), pathway modulation, and synthetic lethality approaches. Furthermore, we identify notable limitations in current research surrounding DDX27 and offer potential avenues for future investigation. These innovative strategies present significant promise for the development of precision cancer therapies aimed at improving treatment outcomes for patients.

Introduction

Helicases are a group of enzymes using the energy from nucleoside triphosphate hydrolysis to unwind the double-stranded DNA–DNA, RNA–DNA, and RNA–RNA molecules into single-stranded nucleic acids. They are also involved in the dissociation of proteins from nucleic acids and chromatin remodelling processes [1–4]. Besides these diverse activities, many helicases play important roles in various processes related to nucleic acid, including DNA replication and repair, homologous recombination, RNA splicing, and telomere maintenance [5–10].

The DDX family is a classic ATP-dependent helicase family, characterized by the presence of a conserved D-E-A-D (aspartic acid-glutamic acid-alanine acid-aspartic acid) sequence [11]. Members of this family contain conserved ATP-binding sites and RNA-binding sites, which are closely related to viral infections, RNA metabolism, and cancer development [12]. Recent studies have pointed out the role of helicases in tumorigenesis, as supported by the high frequency of mutations and abnormal patterns of expression of helicases that demonstrates their functions to drive high proliferation and metabolic rates of cancer cells [7, 13–17]. For example, DDX3 is implicated in various biological processes, including viral manipulation, stress response, hypoxia, radiation response, and apoptosis, and is significantly associated with cancer development and progression. It exerts pro-cancer effects through the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT)-related signals, such as TGF-β, Notch, and Hedgehog pathways [18, 19]. The nuclear export factor Chromosome Region Maintenance 1 (CRM1), associated with DDX3, is significantly implicated in the process of tumorigenesis and may represent a viable target for therapeutic intervention [20]. Additionally, DDX3 exhibits tumor growth inhibitory properties and has the capacity to regulate the transcription of the p21WAF1/CIP1 promoter, positioning it as a potential tumor suppressor [21]. DDX21 is involved in ribosomal RNA processing and interacts with c-Jun N-terminal kinase (c-Jun), facilitating the phosphorylation of c-Jun at the Ser73 site. This interaction enhances the transcriptional activity of activator protein-1 (AP-1), thereby promoting the expression of genes associated with cell proliferation and contributing to breast cancer development [22]. DDX5 is crucial in various biological processes, including cell cycle regulation, embryonic development, cell proliferation, apoptosis, and the occurrence and progression of cancer, as well as responses to viral infections [23]. The prion-like domains of DDX5 plays a certain role in tumors [24]. In non-small cell lung cancer (NSCLC), DDX5 facilitates the nuclear translocation of β-catenin through direct binding, which activates the expression of downstream target genes such as c-Myc and cyclin D1, ultimately promoting tumor cell proliferation and invasion [25]. In gastric cancer, DDX5 enhances tumor cell proliferation by increasing the phosphorylation levels of mTOR and S6K1 [26].

DEAD-box helicase 27 (DDX27) is a member of the DEAD-box RNA helicase family. As a distinct member of the DEAD-box family, DDX27 is capable of regulating multiple stages of RNA metabolism, including transcription [27], alternative splicing [28], protein–protein interactions [29], and translation [30]. Due to its key role in the RNA metabolism process, DDX27 has had a profound impact on numerous biological processes. Dysfunction of this helicase plays a crucial role in various diseases, including IgA nephropathy [31], growth hormone deficiency [32], and multiple cancers [29, 33]. In recent years, DDX27 has attracted considerable scholarly interest owing to its role in the initiation and progression of various solid tumors, indicating its potential as a therapeutic target. Notably, this gene exhibits a direct and substantial influence on cancer progression, distinguishing it from other members of the DDX family (Table 1). The signaling pathways associated with DDX27 have been proven to play an essential role in the development of colorectal cancer (CRC) [29], gastric cancer (GC) [33], breast cancer (BC) [34], hepatocellular carcinoma(HCC) [27, 35], and oral squamous cell carcinoma (OSCC) [36]. For example, DDX27 was reported to regulate the ERK1/2/p53/NF-κB pathway in HCC [27], GC [37] and CRC [29, 38], as well as PI3K/AKT/mTOR pathway in BC [34] and OSCC [39]. Overexpression of DDX27 disrupts such important pathways, leading to the promotion of cancer. This disruption includes the upregulated expression of MVP with DDX27 over-expression in HCC progression [27], consequently facilitating its interaction with ERK, and to further enhance ERK extra-nuclear signaling; the increased interaction between Nucleophosmin 1 (NPM1) and NF-κB-p65 in CRC [29]; the elevation of cellular apoptosis susceptibility protein (CAS/CSE1L) in OSCC [30], by influencing the downstream effector partner proteins of DDX27, resulting in promotion of migration and tumorigenesis. Furthermore, the overexpression of well-established oncogenic or tumor suppressor circular RNA, Circ_RNF13, is attributed to the expression of DDX27, leading to the development of CRC cell stemness and chemoresistance [40]. Recent findings indicate that DDX27 exhibits characteristics associated with cancer mechanisms of through proliferation, migration, and invasion [28, 29]. This suggests that DDX27 may serve as a significant prognostic marker a potential and therapeutic target [28, 29, 34]. Beyond malignancies, DDX27 dysregulation contributes to non-cancer pathologies. In IgA nephropathy, DDX27 is implicated in diagnosis, immune response, and pyroptosis regulation. Integrated machine learning identified DDX27 as a significantly downregulated RNA-binding protein, potentially modulating immune cell infiltration and pyroptosis pathways, offering novel avenues for non-invasive biomarkers [31]. Furthermore, DDX27 is located on chromosome 20q11.22, a genomic region associated with familial growth hormone deficiency (GHD) due to copy number alterations [32]. DDX27 plays a significant role in the regulation of RNA metabolism and genetic alterations, irrespective of whether the context is cancerous or non-cancerous pathology. In tumors, DDX27 facilitates the processing of oncogenic RNA. Conversely, in IgA nephropathy, it may influence immune stability by means of dysregulated RNA binding functions.

Table 1.

The structural and functional differences of DDX helicases in cancer

Helicase	Core structure	Unique domains	Cancer mechanisms	Cellular functions	References
DDX3	RecA1/RecA2 + Q-motif	CRM1	Regulating Wnt/β-catenin signaling and EMT-related signaling	Promote tumor growth and metastasis	[18–20]
			Regulating the transcriptional activity of the p21WAF1/CIP1 promoter	Inhibit tumor growth	[21]
DDX21		c-Jun N-terminal	Promote the phosphorylation of c-Jun at the Ser73 site and the transcriptional activity of AP-1	Promote tumor growth	[22]
DDX5		PrLDs	Activates β-catenin target genes and enhances mTOR/S6K1 phosphorylation	Promote tumor growth and metastasis	[23–26]
DDX27		FxF motif	Regulating the ERK1/2/p53/NF-κB pathway	Promoting tumor growth, metastasis, and drug resistance	[27–29, 37]

CRM1 chromosome region maintenance 1, PrLDs prion-like domains, AP-1 activator protein-1

Recent review, such as the comprehensive study conducted by Zheng et al., systematically summarize the molecular mechanisms by which DDX27 functions in various cancers, evaluating its potential as a clinical prognostic biomarker and its application in novel drug development or therapeutic strategies [41]. Furthermore, contemporary studies have unveiled significant advancements in the structural and functional attributes of DDX27, elucidating its oncogenic molecular mechanisms and offering insights into its subcellular localization and tumor heterogeneity. In light of these developments, the present review aims to synthesize the latest research findings to address critical inquiries regarding the involvement of DDX27 in tumor biology. This review contributes substantially to the field in several key areas: firstly, it underscores the biological roles of DDX27 and its correlations with various diseases; secondly, it investigates the oncogenic mechanisms associated with DDX27 from diverse perspectives, including genetic alterations, epigenetic changes, dynamic subcellular distribution, and pivotal signaling pathways; additionally, it examines the variability of DDX27 expression across different cancer types; finally, it broadens the discourse on DDX27 as a prospective therapeutic target, highlighting the challenges associated with targeting RNA helicases, particularly DDX27, and suggesting new avenues for future research.

Despite the growing biological relevance of DDX27, our comprehension of this protein remains considerably limited. For instance, the RNA/protein interaction interface of DDX27, its conformational dynamics, and the mechanisms underlying its interactions with critical pathways such as PI3K/AKT and p53 have yet to be fully characterized. DDX27 demonstrates opposing roles in various malignant tumors, facilitating tumor progression in certain cancers, including hepatocellular, gastric, colorectal, and breast cancers, while exerting an inhibitory effect in oral squamous cell carcinoma, indicating a significant degree of context dependence; however, its regulatory network has not been thoroughly elucidated. Furthermore, current intervention strategies, including siRNA and shRNA, encounter challenges related to delivery efficiency and off-target effects on homologous proteins, and the role of DDX27 within the tumor microenvironment (TME) and its involvement in immune evasion remain poorly understood.

Overview of DDX27

Structural characteristics of DDX27

DDX27, which is located on chromosome 20q13.13, is a member of DEAD-box RNA helicase family, which is characterized by an Asp-Glu-Ala-Asp (DEAD) amino acid motif [42]. This family is recognized for its high conversation and wide distribution, with DDX27 being expressed in various types of cells [43]. The core structure of DDX27 helicase contains two RecA-like domains (domain 1 and 2), connected by a flexible linker that acts as the binding site for RNA and ATP. The interaction of DDX27 with RNA and ATP induces conformational changes in the protein, which ultimately affect its unwinding activity [44, 45]. In addition, these two RecA-like domains of DDX27 consist of twelve motifs involved in many functions, such as RNA binding(motifs Ia, b, c, IV, IVa, V, and VI), ATP binding and hydrolysis(motifs Q, I, II/DEAD, and VI), and facilitating RNA interaction with the ATP binding site (motifs III and Iva) [46] (Fig. 1). Recent studies have highlighted the Q motif in domain 1, which can form a hydrogen bond with adenine to confer ATP specificity [47, 48]. Some of the other motifs, such as motif Ia and b to motif IV and V [49], sharing functional similarities through structural resemblance.

Fig. 1.

Structure and function of the DDX27 helicase. DDX27 exhibits a modular structure critical for its RNA helicase activity and protein interactions, consisting of three key regions: (1) Highly conserved helicase core (shaded in purple), composed of two RecA-like folds connected by a flexible linker. This core contains 12 evolutionarily conserved motifs that mediate its enzymatic functions: ATP binding and hydrolysis motifs (red): Motif Q (adenine recognition), motif I (ATP binding), motif II (magnesium ion coordination), and motif VI (ATP hydrolysis coupling). RNA binding motifs (blue): Motifs Ia, Ib, Ic, IV, IVa, and V. Coordination motifs (green): Motifs III and Va. (2) N-terminal region (gray, left of the helicase core), containing a partially conserved FxF motif that serves as a docking platform for protein partners (e.g., PeBoW complex, ERK2 kinase) and regulates processes like rRNA maturation and MAPK signaling. (3) C-terminal region (gray, right of the helicase core), involved in nucleolar localization and protein–protein interactions, critical for subcellular targeting and oncogenic signaling. Together, these regions enable DDX27 to orchestrate RNA metabolism and integrate with cancer-related pathways through dynamic interactions

Together with these motifs, DDX27 possesses accessory structural motifs of different lengths and compositions at the N-terminal or C-terminal positions, thereby providing the functional diversity of the protein family [50, 51]. They are located in the flanking regions of the core domains and act as binding sites for specific RNA or protein cofactors. Cargill et al. outlined the diversity in length and composition of these accessory motifs within DEAD-box RNA helicases. Although the exact role of these motifs is not fully understood, the terminal regions of the helicase are thought to confer functional specificity and allow them to be distinguished from each other [52]. For example, within the N-terminal domain of DDX27, there is a motif called FxF that is only partially conserved through evolution from yeast to mammals. It has been shown to interact with the PeBoW complex, which is involved in the 3’end formation of 47S RNAs during rRNA processing [53]. Moreover, the FxF motif serves as a docking platform for the cellular kinase ERK2 and allows it to interact with a variety of proteins. These interactions are not only limited to the transcription factor SAP-1, an ETS2 repressor, but also involve an nuclear pore complex protein Tpr, whereby the interaction greatly increases the target specificity of MAP kinases [54–57]. The accessibility of the FxF docking site could be controlled either by phosphorylation or competition factors [58, 59]. Collectively, the presence of accessory motifs—such as the evolutionarily divergent FxF domain—enables DDX27 to act as a multifunctional scaffold, engaging with diverse molecular partners (e.g., PeBoW complex, ERK2, Tpr) to regulate RNA processing, MAP kinase signaling, and nucleocytoplasmic transport. These interactions, modulated by phosphorylation or competitive binding, ultimately orchestrate cellular processes central to tumorigenesis, including ribosome biogenesis, transcriptional repression (Table 2).

Table 2.

DDX27 and its binding proteins/RNA

Interaction protein	Cancer type	Function	References
MVP	Hepatocellular	Promote the phosphorylation of ERK1/2	[27]
NPM1	colorectal	Promote the transcription and expression of NF-κB downstream target genes	[29]
CSE1L	Oral	Affect cell proliferation and apoptosis	[30]
miRNA-617		Promote the expression of DDX27	[39]

MVP major vault protein, NPM1 Nucleophosmin 1, CSE1L cellular apoptosis susceptibility protein.

As mentioned above, DDX27 exhibits a modular structure that is critical for its biological functions, mainly including the following domains: (1) Helicase Core Domain (conserved functional region). It contains two RecA—like folded domains (purple box in Fig. 2), which form the core of its enzymatic activity. This core harbors 12 conserved motifs responsible for ATP binding/hydrolysis and RNA binding, enabling DDX27 to utilize ATP energy to unwind RNA secondary structures. This function is essential for pre-mRNA splicing, rRNA maturation, and mRNA translation. Cancer-related missense mutations in the core domain (e.g., R502W and R562H in colon cancer) can impair ATPase activity or RNA binding, disrupt helicase function, and drive oncogenic RNA processing reprogramming. (2) Helicase C-Terminal Domain (regulatory functional region). Located downstream of the core domain (red box in Fig. 2), this domain has relatively low conservation but plays a key role in regulating protein–protein interactions and subcellular localization. Truncating mutations in this region (e.g., K689Qfs15 in gastric cancer, K691Rfs4 in breast cancer/colorectal cancer) lead to the loss of regulatory functions, disrupt interactions or localization, and promote malignant phenotypes such as proliferation and metastasis. (3) N-Terminal Region. Mutations affecting this region (e.g., R125Q in breast cancer) can interfere with kinase binding and alter downstream signaling pathways.

Fig. 2.

Mutation hotspot map of DDX27. This map illustrates the distribution of recurrent mutations in DDX27, with structural domains annotated to contextualize their functional impact: Helicase core domains (purple boxes): Correspond to the conserved RecA-like domain 1 and domain 2 in Fig. 1. Missense mutations (blue circles) within this region (e.g., R562H, V292M in colorectal cancer; R125Q in breast cancer) often disrupt ATP binding (motifs Q/I/II) or RNA recognition (motifs Ia/V), impairing helicase activity. Helicase C-terminal domain (red box): Aligns with the C-terminal region in Fig. 1 (right of the helicase core). Truncating mutations (green circles) here (e.g., K689Qfs15 in gastric cancer; K691Rfs4 in colorectal and breast cancer) abolish protein-protein interactions (e.g., with NPM1, MVP) and nucleolar localization, disrupting oncogenic signaling. Mutation types: Missense mutations primarily affect enzymatic function by altering key residues in functional motifs (Fig. 1), while truncating mutations (frameshifts/stop gains) truncate the C-terminal region, losing regulatory domains critical for cancer-related interactions. These mutations are enriched in functionally critical regions, linking structural perturbations to oncogenic phenotypes (e.g., enhanced proliferation, metastasis) across malignancies. The cancer types associated with each mutations. Breast invasive carcinoma: E148*, R125Q, K691Rfs*4, K796N; Colon cancer: V292M, R502W, R562H; Colorectal cancer: R474R, K691Rfs*4; Gastric cancer: K689Qfs*15

Biological functions of DDX27 in cells

DDX27, an essential component of the DEAD-box RNA helicase family, is integral to various aspects of cellular biology. Functioning as an ATP-dependent RNA helicase, DDX27 modulates several phases of RNA metabolism, encompassing transcription, alternative splicing, protein–protein interactions, ribosome biogenesis, translation, and cell cycle regulation. This regulation is achieved through the hydrolysis of ATP, which enables the unwinding of RNA secondary structures [60].

Transcriptional modulation

DDX27 demonstrates aberrant expression patterns in a range of solid tumors and affects the biological characteristics of cancer cells via transcriptional regulation. Recent research suggests that non-coding RNAs are instrumental in the transcriptional regulation of DDX27. In oral squamous cell carcinoma (OSCC), miR-617 transcriptionally activates DDX27 by binding its promoter in a dose-dependent manner, thereby affecting cellular processes such as proliferation, apoptosis, and anchorage-independent growth [39]. Furthermore, DDX27 may increase MVP expression and activate ERK1/2 through the ERK/MAPK signaling pathway, thereby promoting the progression of HCC [27].

Alternative splicing regulation

Members of the DEAD-box protein family are instrumental in cancer progression by influencing the alternative splicing of downstream RNAs [61]. In GC, through mass spectrometry (MS) analysis, DDX27 is involved in regulating the lipoma preferred partner (LPP) protein by affecting the alternative splicing of LPP precursor mRNA (P < 0.05, log₂ fold change < −1). In the Cancer Genome Atlas (TCGA) gastric cancer cohort, high expression of DDX27 is negatively correlated with the LPP transcript that lacks the third exon (LPP-203, LPP-208, and LPP-209). DDX27 can inhibit the skipping of this exon, thereby enhancing the migration and metastasis of gastric cancer cells [28].

Protein–protein interactions

Recent studies indicate that DEAD-box helicases, including DDX27, typically operate as integral components of multi-protein complexes, with their functional activities regulated by their interacting partners [62]. In colorectal cancer (CRC), DDX27 significantly enhances the interaction between nucleophosmin (NPM1) and p65, which subsequently increases the recruitment of NF-κB to the promoters of its target genes. This intensified binding facilitates the transcription and expression of downstream targets of NF-κB, thereby promoting the proliferation of CRC cells, inhibiting apoptotic processes, and fostering metastatic behavior [29].

Translation regulation

DDX27 is critically involved in the regulation of translational processes through its interaction with downstream target genes. DDX27 binds the 5’UTR of CSE1L pre-mRNA to enhance translational efficiency, increasing CSE1L protein levels by 50% without altering mRNA stability. In oral squamous cell carcinoma (OSCC), DDX27 has been demonstrated to interact with CSE1L, which subsequently modulates the expression of CSE1L and influences cellular proliferation and apoptosis [30].

Context-dependent roles in ribosome biogenesis

DDX27 facilitates ribosome biogenesis by promoting 3’-end maturation of 47S pre-rRNA via interaction with the PeBoW complex—a critical step in ribosomal subunit assembly [53]. Furthermore, this function also supports mRNA translation and skeletal muscle regeneration in zebrafish [63]. Recent studies have underscored the context-dependent functional heterogeneity of DDX27. In cell lines derived from gastric cancer (such as AGS and 44As3), quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses revealed that the silencing the DDX27 gene via siRNA does not significantly affect the transcriptional rates of 45S/47S precursor ribosomal RNA or the overall levels of protein synthesis [33]. This finding contrasts with the established role of DDX27 in PeBoW-mediated rRNA processing in normal cells, highlighting its dispensability in gastric cancer models. This notable divergence raises several hypotheses: (1) the ribosome-related functions of DDX27 may require tissue-specific cofactors; (2) alternative RNA helicases may compensate for its absence in certain cellular contexts; (3) the primary role of DDX27 in cancer cells may shift towards non-ribosomal pathways; and (4)the absence of translation defects following DDX27 depletion in AGS/44As3 cells suggests a potential reconfiguration of ribosomal function in the context of malignancy, indicating a significant departure from its previously established role in zebrafish regeneration.

Cell proliferation and cycle control

In addition to its role in RNA metabolism, DDX27 is critically involved in the regulation of cell proliferation by modulating the cell cycle, with effects that differ across various cancer subtypes and genetic backgrounds. In colorectal cancer (CRC), DDX27 depletion increases G1-phase cells while reducing S and G2/M populations [64]. Specifically, in gastric cancer cell lines(such as AGS and 44As3), the knockdown of the DDX27 gene via siRNA for a duration of 96 h led to flow cytometry analyses revealing an increased proportion of AGS cells in the G1 phase and a decreased proportion in the S/G2/M phases. Conversely, 44As3 cells demonstrated a reduction in the S phase alongside an accumulation in the G2/M phase. The disproportionate inhibition of DNA synthesis relative to the decline in proliferation indicates that DDX27 may regulate the cell cycle in gastric cancer in a TP53-dependent manner [33]. In OSCC, silencing of DDX27 results in G2-phase accumulation and a concurrent reduction in the S phase in CAL-27 cells. In contrast, HN6 cells show a decrease in S-phase populations and an increase in the G2/G1 ratio [30]. The impact of DDX27 on the cell cycle exhibits variability that is specific to different cell types, necessitating a contextual analysis of the underlying mechanisms. At the molecular level, the observed differences in G2/M arrest between AGS cells, which possess wild-type TP53, and 44As3 cells, which carry a TP53 mutation, can be attributed to the distinct status of the TP53 gene. Additionally, regarding the microenvironment, 44As3 cells are capable of bypassing G1 checkpoint regulation through the activation of a DNA damage tolerance pathway.

Mechanistic roles of DDX27 in tumorigenesis

DDX27 exhibits its oncogenic characteristics through a complex interplay of genetic alterations, epigenetic modifications, dynamic subcellular localization, and interactions with critical signaling pathways.

Genetic alterations: DNA copy number alterations (CNA) and hotspot mutational landscape

DNA copy number alterations (CNA) and tumor development

DNA copy number alterations (CNA) are a significant component in the evaluation of genomic instability, as they can influence the functional expression of specific genes, thereby establishing a connection to tumorigenesis and the progression of malignancies [65]. The amplification of chromosome 20q, which is a hallmark of genomic instability across various cancers such as hepatocellular carcinoma (HCC), colorectal cancer (CRC), and breast cancer (BC), is recognized for its role in promoting the overexpression of the DDX27 gene [35, 66, 67]. In HCC, CNAs within this chromosomal region are frequently observed and may increase the likelihood of metastasis and mortality, highlighting their prognostic relevance [35]. The overexpression of the DDX27 gene in CRC is likely a consequence of elevated DNA copy numbers, which contribute to a pro-carcinogenic milieu [29]. Additionally, in gastric cancer (GC), the methylation status of DDX27 displayed a bimodal distribution, indicating a significant correlation between its expression levels and mRNA copy number alterations (CNA).This suggests that CNAs may act as enhancers of gene expression [68].

Hotspot mutations in DDX27 associated with tumor occurrence and progression

Mutations of helicase may potentially disrupt normal RNA processing, which lead eventually to the development of cancers [69]. In the case of DDX27, these mutations often affect the functions of the enzyme rather than its expression level (Fig. 2). Therefore, individuals with mutated DDX27 could be predisposed to the different types of tumor as tabulated below (Table 3).

Table 3.

Summary of identified somatic mutations in DDX27 gene

Study characteristics (author, year,cohort, database)	Total number	DDX27 Mutation rate (%)	Cancer type	Amino acid change	Mutation type	Copy	Mutation assessor	References
No Author, 01/09/2024, TCGA-CRC	276	2.20	Colorectal	K691Rfs*4	truncating	Diploid		[29]
			Colorectal	K691Rfs*4	truncating	Gain
			Colon	R562H	Missense	Diploid	Low
			Colorectal	R474R	Missense	Diploid	Neutral
			Colon	V292M	Missense	Diploid	Medium
			Colon	R502W	Missense	Gain	High
Guoetal, 01/09/2024, cBioportal database	147	3.40	Gastric	K689Qfs*15	truncating	Gain	Not reported	[28]
				K689Qfs*15	truncating	Diploid
				K689Qfs*15	truncating
				K689Qfs*15	truncating
				K689Qfs*15	truncating
No Author, 01/09/2024, firehoselegacy, TCGA-BRCA	1108	0.50	Breast Invasive Carcinoma	K691Rfs*4	truncating	Diploid	Not reported	[34]
				K691Rfs*4	truncating	Gain
				K691Rfs*4	truncating	Diploid
				E148*	truncating	Gain
				R125Q	Missense	Diploid
				K796N	Missense	Diploid

DDX27 mutations identified from the data analysis of the Cancer Genome Atlas (TCGA) CRC cohort, were present in only 2.2% of cases (6 out of 276). Notably, two of these cases showed a truncating mutation at the K691 site (K691Rfs*4), while the remaining four had missense mutations causing single amino acid substitutions (R562H, K474R, V292M, and R502W). These findings offer detailed insights into the genetic complexity of CRC and reinforce the potential role of DDX27 in the pathogenesis [29].

Similarly, data from the cBioPortal database also revealed a relatively low mutation rate of DDX27 in gastric cancer (GC), with mutations detected in only 3.4% of cases (5 out of 147). All five cases had a truncating mutation (K689Qfs*15). Although DDX27 mutations are rare in GC, they can result in early termination of translation, significantly impairing the protein function and contributing to tumorigenesis [28]. Furthermore, data from the TCGA-BRCA cohort showed an even lower mutation rate of 0.5% (6 out of 1108) in BC. These are four truncating mutations: three at position K691 (K691Rfs*4) and one at position E148*, together with two missense mutations (R125Q and K796N). Given the relationship of DDX27 with BRCA1 and its DNA repair function [34], the genetic instability caused by these mutations strongly promotes uncontrolled cell proliferation, migration and invasion, thereby fostering the development and progression of cancer.

Epigenetic regulation: DNA methylation and miRNA interactions

Epigenetic regulation pertains to the modulation of gene expression without any changes to the fundamental DNA sequence. This encompasses various mechanisms, including post-translational modifications such as DNA methylation and histone modifications (including methylation), in addition to chromatin remodeling [70].

DNA methylation

The DDX27 gene exhibits a distinct bimodal distribution pattern of methylation, with its differential expression demonstrating statistical significance (P = 2.43e−16). Additionally, copy number alterations (CNA) show a significant correlation with mRNA expression, suggesting that CNA may function as a primary mechanism influencing DDX27 expression. Notably, an analysis of the high methylation subgroup indicates that in Subgroup 1, DNA methylation is positively correlated with CNA (P = 2.42e−3), implying that methylation may indirectly affect gene expression through the modulation of CNA. These findings highlight the role of epigenetic mechanisms in regulating DDX27 expression in gastric cancer [68]. Moreover, the interaction between CNA, DNA methylation, and DDX27 is crucial in the regulation of gene expression.

miRNA interactions

In OSCC cells (such as SCC131 cells), the expression of miR-617 is markedly diminished due to extensive methylation of its promoter (P < 0.01). Dual-luciferase reporter assays have demonstrated that miR-617 interacts with the DDX27 promoter in a dose-dependent manner, thereby positively influencing its expression (P < 0.05). Furthermore, reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis of samples from 36 OSCC patients revealed that 16 out of 36 (44.4%) displayed consistent alterations in the expression levels of miR-617 and DDX27, characterized by synchronous upregulation or downregulation. This finding suggests that the regulatory relationship between these two entities is of biological significance (P < 0.05) [39].

Collectively, the expression and functionality of DDX27 are influenced by a range of mechanisms, including chromosomal copy number alterations (CNA), mutations, epigenetic modifications, and the regulatory effects of microRNAs.

Subcellular localization of DDX27 protein in normal and cancer cells

In normal cells, DDX27 interacts with RNA through its C-terminal domain to achieve nucleolus-specific localization and is directly involved in the maturation process of ribosomal RNA. This protein associates with the PeBoW complex through its N-terminal FxF motif; however, this interaction does not influence its mechanism of nucleolar localization [53]. Immunofluorescence co-localization analysis have demonstrated that DDX27 is specifically distributed within the nucleolus of GC cells. Following treatment with epirubicin, DDX27 was observed to translocate from the nucleolus to the nucleoplasm, where it formed aggregates that partially co-localized with γ-H2AX. Additionally, there was a significant increase in the nucleoplasmic fraction of DDX27. These findings suggest that DDX27 is actively involved in the DNA damage response pathway through its dynamic relocalization, thereby contributing to tumor progression [68]. Although there are some discrepancies regarding its precise localization, the presence of DDX27 in the nucleolus strongly indicates a relationship with its RNA-dependent helicase activity, akin to other helicases, including DDX3 [53]. In contrast to DDX3, which has been observed in centrosomes and mitochondria [20, 71–73], there is currently no evidence to suggest that DDX27 is localized in the centrosome, mitochondria, or other RNA/protein complexes.

DDX27-mediated regulation of oncogenic signaling pathways in cancer

DDX27 plays a pivotal role in the regulation of oncogenic signaling by engaging in dynamic interactions with fundamental pathways, including NF-κB, ERK, PI3K/AKT/mTOR, and p53, as well as with various protein partners such as LPP, NPM1, MVP, and CSE1L. Through the coordination of transcriptional regulation, splicing mechanisms, and post-translational modifications, DDX27 facilitates processes associated with cancer initiation, metastasis, stemness, and resistance to therapeutic interventions [62, 74]. The context-dependent functions of DDX27 are comprehensively summarized in Table 4 and illustrated in Fig. 3.

Table 4.

Oncogenic/tumor-suppressive role of DDX27in various cancers

Cancer typer	Oncogenic/tumor-suppressive	Mechanism/pathway	Cellular functions	Clinical vaule	References
Gastric	Oncogenic	Promoting drug resistance through nucleoplasmic translocation Promotes proliferation through the p53 pathway Promotion of invasion and metastasis through the DDX27/LPP/EMT axis	Regulates RNA alternative splicing; Promotes EMT process; Affects DDX27/LPP/EMT regulatory axis; Regulates cell cycle and epirubicin resistance;	Diagnostic Prognostic Therapeutic target	[28] [33] [68]
Colorectal	Oncogenic	Promotion of proliferation through the DDX27/NPM1/NF-κB axis Promotion of invasion and metastasis by EMT Promotes stem cellularity through the circRNF13/TRIM24/DDX27 axis	Promotes protein–protein interactions; Regulates cell cycle and 5-FU resistance; Promotes EMT process; Interacts with NPM1 and p65; Regulates NF-κB signaling pathway; Regulates stem cell activity;	Prognostic Therapeutic target	[29] [40] [64]
Hepatocellular	Oncogenic	Promotion of proliferation through the DDX27/MVP/ERK pathway	Regulates transcription; Regulate the phosphorylation level of ERK1/2; Promoting proliferation and metastasis;	Prognostic	[27]
Breast	Oncogenic	DDX27 promotes cell proliferation and migration by regulating NF-κB, p53, PI3K/AKT/mTOR signaling pathways	Promotes metastasis, proliferation and stemness;	Prognostic Therapeutic target	[34]
Oral	Oncogenic	Promote proliferation and migration through DDX27 interacts with CSE1L	Regulates translation and cell cycle; Promotes EMT process and proliferation;	Prognostic Therapeutic target	[30]
	Tumor-suppressive	miR-617 regulates DDX27 levels through the PI3K/AKT/mTOR pathway	Regulates transcription; Reduce activation PI3K/AKT/mTOR pathway; Regulates cancer hallmarks;		[39]

5-FU 5-fluorouracil, LPP lipoma-preferred partner, NPM1 Nucleophosmin 1, EMT epithelial-mesenchymal transition

Fig. 3.

DDX27 and cancer signaling pathways. DDX27 is strongly associated with the process of cancer and impacts them in a direct ways. DDX27 promotes HCC proliferation and metastasis by increasing levels of MVP, and further elevating the phosphorylation of ERK1/2. DDX27 regulates LPP protein expression by reducing the SE event on the third exon of LPP transcripts, enhancing the translation of functional domain-containing LPP protein. This regulation via the DDX27/LPP/EMT axis promotes gastric cancer progression. DDX27 also reduces the proportion of cells in the G1 phase while increasing the proportion in the S and G2/M phases, thereby regulating the cell cycle and promoting cell proliferation and tumor progression in GC. In CRC, DDX27 markedly increases the interaction between NPM1 and p65, which promotes the transcription and expression of NF-κB downstream targets, thereby facilitating CRC cell proliferation and metastasis. Meanwhile, it upregulates the expression of cancer stem cell markers (e.g., CD44, CD133, EpCAM, LGR5), enhances CSC self-renewal capacity. It can increase Slug, vimentin and decrease E-cadherin resulting to EMT. In BC, DDX27 promotes expression of OCT4 thereby leading to stem cell like properties as well as increasing the PI3K-AKT-mTOR and p53, leading to metastasis, proliferation and stemness. DDX27 upregulation results in increased cell proliferation and metastasis by upregulating Ki-67, N-cadherin, and vimentin, and inducing cell cycle, decreased apoptosis via inhibiting Bax. CSCs: cancer stem cells.

Epithelial-mesenchymal transition (EMT) and metastasis

Epithelial-mesenchymal transition (EMT) drives tumor metastasis through characteristic molecular shifts, including N-cadherin upregulation and E-cadherin downregulation [75]. In GC, DDX27 promotes epithelial-mesenchymal transition (EMT) by regulating the splicing of LPP precursor mRNA, leading to increased expression of wave protein/N-cadherin and decreased expression of ZO-1/E-cadherin. In AGS cells, Trans-well assays and Wound healing assays revealed that this mechanism enhances the invasion and metastatic capabilities of gastric cancer cells (P < 0.001, P < 0.01, by ANOVA) [28]. In CRC, DDX27 promotes proliferation and metastasis by upregulating vimentin/Slug and downregulating E-cadherin through NPM1 interaction, thereby activating NF-κB and EMT pathways [29]. In OSCC, DDX27 collaborates with CSE1L to promote tumor progression through a dual mechanism: (1) upregulating proliferation markers (Ki-67) and mesenchymal proteins (vimentin, N-cadherin); (2) downregulating the pro-apoptotic protein Bax and the epithelial marker E-cadherin. This regulation of the EMT process and the proliferation-apoptosis balance significantly enhances metastatic potential [30].

Stemness and chemoresistance

DDX27 critically maintains cancer stemness and chemoresistance across malignancies. DDX27 knockdown significantly reduced expression of cancer stem cell markers (CD44, CD133, EpCAM, LGR5). In vitro, it enhanced sensitivity to 5-fluorouracil in HCT116 and HT29 colorectal cancer cells, increasing apoptotic cell death by approximately 2.2-fold and 1.6-fold, respectively, as shown by flow cytometry analysis [64]. Research conducted by Yi et al. demonstrates that circ_RNF13 plays a crucial role in stabilizing TRIM24 by inhibiting its degradation mediated by FBXW7. This stabilization subsequently enhances the transcriptional activation of DDX27 by TRIM24, thereby influencing the stem cell characteristics and chemotherapy sensitivity in colorectal cancer [40]. In 14 GC cell lines, In silico analysis showed that the expression level of DDX27 was significantly positively correlated with the IC50 value of epirubicin (P = 0.01, t-test), indicating that high expression of DDX27 may mediate chemotherapy resistance [68]. DDX27 overexpression correlates with resistance to 5-fluorouracil (5-FU) in CRC and epirubicin in GC [64, 68]. These findings collectively highlight DDX27 as a central mediator of stemness and therapeutic resistance across malignancies.

Context-dependent oncogenic network integration

DDX27 functions as a molecular hub integrating key oncogenic pathways in a cancer-type-specific manner. In breast cancer, gene set enrichment analysis (GSEA) indicates that DDX27 plays a significant role in promoting cell proliferation and migration through the modulation of the NF-κB (P < 0.0001), p53 (P < 0.0001), and PI3K/AKT/mTOR (P < 0.0001) signaling pathways. This finding highlights potential targets for therapeutic intervention [34]. By constructing a nude mouse xenograft model, it was observed that the tumor volume generated by DDX27 knockout HepG2 cells was markedly smaller compared to that of the control group (P < 0.05). Additionally, there was a significant reduction in the expression level of MVP. These findings provide further evidence that DDX27 facilitates the progression of hepatocellular carcinoma (HCC) through the upregulation of MVP expression and the activation of the ERK1/2 signaling pathway [27]. Conversely, In contrast, the suppression of DDX27 mediated by miR-617 inhibits the PI3K/AKT/mTOR signaling pathway in oral squamous cell carcinoma (OSCC), thereby demonstrating tumor-suppressive properties [39].

The functional versatility of DDX27 arises from its capacity to integrate several processes: (1) genetic and epigenetic modifications, (2) the shuttling of molecules between the nucleolus and nucleoplasm, (3) helicase-dependent RNA processing, which includes ribosomal RNA maturation, DNA repair, and alternative splicing, and (4) context-dependent interactions with various partners such as MVP, NPM1, CSE1L, and TRIM24. Collectively, DDX27 plays a pivotal role in oncogenesis through multiple mechanisms that promote cellular proliferation, metastasis, stemness, and resistance to chemotherapy.

DDX27 in cancer: expression patterns and clinical relevance

DDX27 demonstrates significant upregulation in a range of malignancies and plays a role in the emergence of aggressive oncogenic characteristics, including enhanced proliferation, metastasis, chemoresistance, and stemness. This section consolidates the expression profiles of DDX27 across different malignancies and examines their associations with clinicopathological features. To provide a concise and comprehensive overview. Key findings are synthesized below and summarized in Table 5.

Table 5.

Expression of DDX27 in various cancers

Cancer type	mRNA/protein	High/low expression	Role in cancer	Cell lines	In vivo models	Relevant clinical factors	Relationship with patient survival and prognosis	References
Gastric	mRNA and Protein	High	Promotive	AGS, 44As3, BGC-823	Nude mouse xenografts	Depth of tumor invasion,venous invasion,lymph node metastasis,distant metastasis, vascular invasion, intestinal-type	Independent prognostic factor for OS and CSS	[28] [33] [68]
Colorectal	mRNA and Protein	High	Promotive	HCT116, HT29, SW480	Nude mouse xenografts	Tumor location	Independent prognostic factor for OS and RFS	[29]
hepatocellular	mRNA and Protein	High	Promotive	HepG2, PLC	mouse xenografted model	Vascular invasion	Independent prognostic factor for OS and DFS	[27]
Breast	mRNA and Protein	High	Promotive	MCF-7, T47D	NA	larger tumor size, positive lymph nodes, higher ki-67, higher histological grade and later TNM stage	Independent prognostic factor for OS and DFS	[34]
oral squamous cell carcinoma	mRNA and Protein	High	Promotive	CAL-27, HN6	Nude mouse xenografts	pathological grade	Worse OS	[30]
			Inhibitive	SCC131, SCC084	Nude mouse xenografts	NA	NA	[39]

OS overall survival, CSS cancer-specific survival, RFS relapse-free survival, DFS disease-free survival, “NA” represents Lack of research

Pan-cancer overexpression

In various malignancies, methodologies such as immunohistochemistry (IHC), quantitative polymerase chain reaction (qPCR), and Western blotting have been utilized to evaluate the expression levels of DDX27 mRNA and protein in tissue or cellular samples obtained from gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC), breast cancer (BC), and oral squamous cell carcinoma (OSCC). The results consistently indicated a significant increase in DDX27 levels in comparison to adjacent normal tissues or cells (P < 0.05). Moreover, comprehensive data mining performed using public databases, including The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), further substantiated these findings. For example, analysis of the gastric cancer GEO dataset (GSE13911) revealed a statistically significant difference between tumor and normal samples (P < 0.001, t-test). Similarly, colorectal cancer data from TCGA (tumor vs. normal, P < 0.0001) and GEO (tumor vs. normal, P < 0.0001) corroborated this observation. Additionally, breast cancer data from TCGA demonstrated a notable difference (t = 14.713, P < 0.0001), while oral squamous cell carcinoma data from GEO (GSE42743) indicated a significant disparity (tumor vs. normal, P < 0.01). Collectively suggesting that DDX27 expression is statistically distinct from that of adjacent normal tissues [27, 30, 33, 34, 64]. Collectively, these findings suggest that DDX27 expression is statistically distinct from that of adjacent normal tissues.

Tissue-specific clinicopathological correlations

From a pathological perspective, the overexpression of DDX27 in gastric cancer (GC) demonstrates a significant positive correlation with several clinical parameters, including invasion depth (P = 0.000479), lymph node metastasis (P = 0.043427), distant organ metastasis (P = 0.0159), vascular invasion (P = 0.0016), and Lauren classification, particularly in intestinal-type cancers (P = 2.9e−04, t-test), where its expression is markedly elevated. However, no statistically significant difference in DDX27 expression was identified between the early (stages 1 & 2) and late (stages 3 & 4) disease groups (P = 0.85, Fisher’s exact). This finding is consistent with the results reported by Shihori et al. in their investigation of gastric cancer [28, 33, 68]. Additionally, the expression levels of DDX27 are significantly influenced by the anatomical location of the tumor. Specifically, DDX27 expression is lower in colon cancer compared to rectal cancer (P < 0.001), a finding supported by data from the TCGA cohort. It is noteworthy that the expression levels of DDX27 in both tumor types are significantly higher than those in adjacent normal tissues (both P < 0.001) [29]. In a cohort of 165 breast cancer cases, univariate analysis indicated a significant positive correlation between DDX27 expression and tumor size (P = 0.0005), positive lymph nodes (P = 0.0008), higher histological grade (P = 0.0040), Ki-67 positivity (P = 0.0063), and advanced TNM staging (P < 0.0001) [34]. In OSCC, Spearman rank correlation analysis revealed a significant positive correlation between DDX27 expression levels and advanced histological grade (P < 0.01) [30]. In hepatocellular carcinoma (HCC), DDX27 overexpression is significantly associated only with vascular invasion (P = 0.03), and does not exhibit a significant correlation with tumor size (P = 0.143), alpha-fetoprotein (AFP) expression (P = 0.163), or tumor staging (P = 0.235) [35].

The heterogeneity of DDX27 in different cancer types

The expression, function, and prognostic implications of DDX27 exhibit variability across different cancer types. For example, in colon cancer, increased DDX27 expression is associated with a decrease in survival duration (P < 0.05). In contrast, rectal cancer studies have shown no statistically significant difference in survival times between groups with high and low DDX27 expression levels [29]. In OSCC, the positivity rate for DDX27 in tumor tissues is 49.1% (27/47), whereas it is undetectable in normal mucosal tissues (5/5). This finding suggests notable differences in DDX27 expression among tumor samples, indicating expression heterogeneity, which aligns with the research conducted by Neelanjana Sarkar [30, 39]. Additionally, factors within the tumor microenvironment, such as hypoxia, may modulate the expression and functionality of DDX27, thereby influencing tumor progression. In breast cancer, DDX27 expression is closely linked to the hypoxia pathway and may be related to the development of oxidative stress responses [34]. Furthermore, DDX27 demonstrates cell cycle regulatory heterogeneity across various cancer models, including gastric (AGS, 44As3) and OSCC(CAL-27, HN6) cell lines [30, 33]. This variability may be significantly related to the differing expression levels observed in distinct cell types, as well as the regulatory mechanisms and interactions with other molecular entities. Such context-dependent factors highlight the importance of developing tumor-type-specific therapeutic strategies that account for the heterogeneity observed among patients.

DDX27: an emerging dual-role biomarker for cancer diagnosis and prognosis

The overexpression of DDX27 in various malignancies has been associated with aggressive cancer phenotypes, thereby establishing it as a potential biomarker for both diagnosis and prognosis (Tables 3, 4). For example, DDX27 overexpression is observed in 27.8% of gastric carcinomas (P = 2.43e−16, t-test), with a prevalence of 50% in stage I tumors (P = 1.07e−04, t-test), indicating its potential as an early diagnostic biomarker. Initial Kaplan–Meier analyses reveal that gastric cancer patients exhibiting high levels of DDX27 expression demonstrate significantly poorer cancer-specific survival (CSS) (P = 0.0021, by log-rank test) and overall survival (OS) (P < 0.001, by log-rank test) [28, 33, 68]. A cohort study conducted in Beijing employed Kaplan–Meier curves and multivariate regression analysis to illustrate that increased levels of DDX27 mRNA expression is significantly correlated with relapse-free survival (RFS) in colorectal cancer patients (P < 0.05). Moreover, DDX27 mRNA expression was identified as an independent prognostic factor linked to reduced relapse-free survival (RFS) (P < 0.05; hazard ratio: 2.667, 95%CI: 1.116–6.374). In a cohort from Shanghai, a higher density of DDX27 staining in primary colon cancer tissues (score ≥ 8) was associated with decreased in overall survival rates((N = 260, P < 0.05) [29]. Further analyses using Kaplan–Meier methods and log-rank tests on 165 breast cancer patients, 126 hepatocellular carcinoma patients, and a cohort of 74 oral squamous cell carcinoma patients from the GEO database (GSE42743) revealed a significant positive correlation between DDX27 expression and reduced overall survival (OS) (BC, P = 0.0087; HCC, P < 0.0005; OSCC, P < 0.05). Additionally, DDX27 expression was closely linked to diminished disease-free survival (DFS) (BC, P = 0.0235; HCC, P < 0.005) [27, 30, 34]. Ultimately, DDX27 overexpression has been shown to mediate chemoresistance to agents such as epirubicin and 5-fluorouracil, thereby compromising treatment efficacy and prognostic outcomes [64, 68].

In summary, the expression levels of DDX27 are significantly correlated with tumor progression, clinical outcomes, and therapeutic responses, highlighting its potential as a dual-function biomarker for diagnostic and prognostic evaluations. Despite strong preclinical evidence supporting the potential of DDX27 as a biomarker, its clinical applicability remains under investigation. Currently, there are no registered human validation studies or active clinical trials focusing on DDX27, underscoring the necessity for future prospective cohort studies.

Therapeutic targeting of DDX27 in cancer: emerging strategies

DDX27 is integral to the facilitation of oncogenic cellular functions and tumor progression, as well as impacting clinical outcomes such as prognosis and treatment effectiveness. Preclinical studies have identified DDX27 as a promising therapeutic target. As a result, an enhanced understanding of its molecular mechanisms has spurred the development of DDX27-targeted therapies, uncovering novel pathways and targets for precision oncology. This section delineates innovative therapeutic strategies aimed at DDX27, which encompass the silencing of DDX27 via siRNA or shRNA, modulation of signaling pathways, the application of miR-617 mimics, and genetic therapeutic approaches, including those based on the concept of synthetic lethality.

RNA interference-mediated DDX27 knockdown

In GC, RNA interference techniques employing short interfering RNA (siRNA) or short hairpin RNA (shRNA) have been demonstrated to effectively inhibit the expression of DDX27, thereby reducing the tumor’s ability to form colonies [33]. Zhou et al. provided evidence that the overexpression of DDX27 contributes to epirubicin resistance in 14 gastric cancer cell lines. Furthermore, the subsequent knockdown of DDX27 restored the sensitivity of resistant cells to apoptosis induced by epirubicin [68]. In colon cancer, the downregulation of DDX27 has been linked to enhanced sensitivity to 5-fluorouracil (5-FU), underscoring its potential as a promising therapeutic target [64].

Pathway modulation

DDX27 has been identified as a significant factor in various tumor signaling pathways. In hepatocellular carcinoma (HCC), the DDX27/MVP/ERK1/2 signaling pathway is instrumental in promoting the progression of the disease. The use of ERK pathway inhibitors, such as SCH772984, has demonstrated a reduction in the migratory of cells influenced by DDX27 [27]. In colon cancer, the DDX27/NPM1/NF-κB axis is crucial for in regulating tumor progression, and the application of NF-κB inhibitors, including CAPE and JSH-23, has been effective in alleviating the oncogenic effects associated with the overexpression of DDX27 [29]. These therapeutic strategies may exhibit a certain level of efficacy in patients with DDX27 overexpression. Currently, while inhibitors targeting the ERK/NF-κB pathways have shown effectiveness in specific malignancies, such as colorectal cancer (CRC) with agents like Ulixertinib and lung cancer with compounds like LY3214996 [76–79]. The full implications of DDX27-specific signaling pathways remain inadequately understood. Moreover, existing therapeutic interventions do not completely inhibit these pathways. In both HCC and CRC, DDX27 promotes tumor progression through a distinct regulatory axis involving MVP/ERK/NF-κB, which differs from conventional ERK/NF-κB inhibition mechanisms. Future investigations should prioritize the development of DDX27-specific inhibitors, such as small interfering RNA (siRNA) or small molecules, and evaluate their therapeutic efficacy in preclinical models of HCC and CRC.

miRNA-based therapy

MicroRNAs (miRNAs), which are classified as non-coding RNAs, play a crucial role in the regulation of gene expression through their interactions with target messenger RNAs (mRNAs). The dysregulation of miRNA expression is a prominent feature of cancer, where these molecules can function either as oncogenes or tumor suppressors [80]. For example, in oral squamous cell carcinoma (OSCC), miR-617 has been shown to upregulate DDX27 while simultaneously inhibiting the PI3K/AKT/mTOR signaling pathway, thereby exerting anti-tumor effects. This finding suggests that synthetic miR-617 mimics may serve as potential therapeutic agents for OSCC [39].

Synthetic lethality

Genetic strategies, such as synthetic lethality (SL) and synthetic dosage lethality (SDL), utilize gene interactions as therapeutic approaches, showing notable effectiveness in cancer treatment. These mechanisms specifically target cancer cells that display deficiencies in DNA repair, while preserving the integrity of normal cells. Furthermore, additional members of the DEAD/H-box helicase family, including DDX3, DDX9, and DDX41, have shown potential in reducing adverse effects and facilitating the clinical application of innovative therapies. Nevertheless, to date, there has been no published research concerning the application of these strategies to DDX27 [81].

Discussion and future perspectives

Context-dependent molecular functions of DDX27 in malignancies

The evidence presented in this review positions DDX27 as a complex oncogenic driver that integrates genetic, epigenetic, and oncogenic signaling pathways to facilitate tumorigenesis across various malignancies. Although DDX27 shares fundamental RNA helicase functions with other members of the DEAD-box family, its distinctive structural characteristics, particularly the accessory N-terminal FxF motif and C-terminal regulatory domains, allow for tissue-specific interactions with RNA and protein partners, thereby broadening its roles in cancer biology [53]. For example, in colorectal cancer (CRC), DDX27 enhances NF-κB signaling through its interaction with NPM1 [29], while in hepatocellular carcinoma (HCC), it activates ERK1/2 via the upregulation of MVP [27]. These context-dependent mechanisms likely stem from variations in cofactor availability and post-translational modifications, highlighting the necessity for cancer-type-specific functional analyses. In gastric cancer (GC)-derived cell lines, DDX27 is involved in ribosomal RNA processing; however, its depletion in GC cell lines does not appear to affect global translation [33]. Traditionally, DNA methylation has been associated with transcriptional silencing, however, hypermethylation of DDX27 correlates with increased expression in certain gastric cancers, challenging conventional models [68].

This paradox indicates context-dependent roles for DNA methylation in cancer. Under pathological conditions, methylation may facilitate transcriptional activation via mechanisms such as transcription factor competition or chromatin remodeling. We propose that methylation may create binding sites for transcriptional activators or remodel chromatin architecture to facilitate enhancer-promoter interactions. Validating this through methylated DNA immunoprecipitation sequencing (MeDIP-seq) in primary samples is critical. Such non-canonical regulation likely contributes to tumor evolution, warranting investigation into methylation’s dual functions.

Model limitations and advanced systems for functional validation

Moreover, current experimental models present significant limitations for validating DDX27’s context-dependent functions. In vitro systems (e.g., GC cell lines) fail to recapitulate human tumor microenvironment (TME) interactions, while xenografts lack patient-specific immune contexts. These constraints may underlie observed discrepancies in DDX27’s cell cycle effects across models. To address this, patient-derived organoids (PDOs) and PDX models with CRISPR-Cas9 DDX27 editing should be prioritized [82, 83]. The spatial mapping of DDX27-nucleoprotein complexes utilizing CODEX/MIBI-TOF techniques can elucidate their expression patterns within various tissues. Functional validation of the DDX27-mediated immune interactions within humanized tumor microenvironment contexts. High—throughput screening of DDX27-dependent therapeutics.

Clinical translation challenges and research imperatives

Clinically, DDX27 overexpression is consistently linked to advanced tumor staging, metastasis, and poor survival outcomes across various carcinomas [28, 33]. The nuclear enrichment of DDX27 in malignant tissues compared to normal tissues enhances diagnostic specificity; however, challenges such as intratumoral heterogeneity and the necessity for antibody validation continue to pose considerable challenges. Notably, DDX27 serves as a dual biomarker for chemoresistance (e.g., to epirubicin in gastric cancer and 5-FU in colorectal cancer) and stemness properties, suggesting that its expression levels may serve as a predictive indicator for chemotherapeutic sensitivity in patients [40, 64, 68]. However, the existing evidence predominantly stems from retrospective studies, and it is imperative to conduct prospective validation within multicenter cohorts to establish its clinical applicability.

From a therapeutic perspective, while siRNA/shRNA strategies show preclinical promise [33, 68], clinical translation is hampered by delivery challenges and off-target effects on homologous helicases. Emerging solutions include—mediated delivery, proteolysis-targeting chimeras and CRISPR-Cas9 screens, may enhance specificity [84–86]. Additionally, the synthetic lethality approach represents a precision treatment modality in oncology that selectively targets cancer cells by exploiting their genetic vulnerabilities while minimizing harm to normal cells. Nevertheless, the moderate mutation frequency of DDX27 (2.2% in CRC and 3.4% in GC) underscores the need for combination therapies that target downstream effectors, such as NF-κB and ERK. Significant advancements have been made in understanding the molecular mechanisms and regulatory networks associated with DDX27; however, several critical limitations remain. Firstly, mechanistic clarity regarding RNA/protein interfaces, conformational dynamics, and PI3K/AKT/p53 pathway crosstalk. Secondly, context-dependent functionality, where DDX27 paradoxically acts as an oncogene in HCC but tumor suppressor in OSCC [27, 39], which may be influenced by different signaling pathways, unidentified tumor microenvironments. Thirdly, unvalidated diagnostic potential in preneoplastic lesions (e.g., gastric dysplasia). Lastly, limited clinical translation of therapeutic strategies and unexplored immunomodulatory roles in angiogenesis, immune evasion, and inflammation.

Multiscale dissection of DDX27: atomic landscapes to clinical translation

To address these limitations and leverage emerging technologies, we propose a systematic roadmap that encompasses atomic-scale mechanistic studies leading to clinical translation, with a focus on innovative methodologies and interactions within the tumor microenvironment. The oncogenic functions of DDX27 can be comprehensively analyzed through integrative approaches that include atomic-scale structural biology, dynamic molecular tracking, and multi-omics technologies. For example, cryo-electron microscopy (cryo-EM) [87] facilitates high-resolution structural investigations of DDX27 in complex with critical partners, such as NPM1 and MVP, thereby revealing conformational alterations in its RNA-binding domains. Additionally, single-molecule fluorescence tracking [88] can provide insights into the nucleolar-nucleoplasmic shuttling dynamics of DDX27 and its transient interactions with chemotherapeutic agents like epirubicin. Concurrently, artificial intelligence (AI) [89] enhanced molecular dynamics simulations can predict how specific hotspot mutations, such as K691Rfs*4, disrupt ATPase activity and RNA unwinding efficiency, offering mechanistic insights into mutation-driven oncogenicity.

Within the tumor immune microenvironment, single-cell RNA sequencing (scRNA-seq) can elucidate the heterogeneity of DDX27 expression across malignant cells, tumor-associated macrophages (TAMs), and exhausted T cells, correlating its expression levels with immunosuppressive phenotypes. To functionally validate these associations, DDX27-knockout tumor organoids can be co-cultured with CAR-T/NK cells, allowing for a quantitative assessment of DDX27’s role in immune evasion. For precision oncology applications, multimodal AI diagnostic models can integrate ctDNA-based DDX27 mutations and copy number alterations (CNAs), exosomal proteomics, and radiomic features to enhance early cancer detection and prognostic stratification [90]. Given that DDX27 is regulated by ERK and NF-κB pathways, patient-derived organoid (PDO) [91] biobanks can serve as effective platforms for high-throughput screening of DDX27-dependent therapeutics, prioritizing compounds that synergize with pathway inhibitors. Spatial proteomics technologies, such as CODEX and MIBI-TOF [92, 93], can map the spatial co-localization of DDX27 with phosphorylated ERK/NF-κB signaling hubs at subcellular resolution, although challenges related to high costs, complex sample preparation processes, difficulties in data analysis, and insufficient detection sensitivity for low-abundance targets [94, 95]. Complementary single-cell epigenomic profiling techniques, including scATAC-seq and scChIP-seq [96], can elucidate DDX27-mediated chromatin accessibility and enhancer remodeling, linking its epigenetic regulation to transcriptional reprogramming in cancer.

In the realm of AI-driven drug discovery, AlphaFold utilizes deep learning algorithms to predict high-accuracy protein structures by analyzing amino acid sequences, interatomic distances, and peptide bond geometries, thereby establishing a computational framework essential for structure-based drug design [97]. The structures predicted by AlphaFold for DDX27’s ATP-binding pocket can expedite the virtual screening of helicase inhibitors, while generative adversarial networks (GANs) can optimize drug permeability and target engagement. However, successful clinical translation will require multicenter validation to confirm the diagnostic and therapeutic utility of DDX27 across diverse populations.

Translating DDX27 biology to precision oncology

Research on DDX27 is evolving from discrete molecular observations to a comprehensive theoretical framework, facilitated by the integration of cryo-electron microscopy, single-cell multi-omics, spatial analysis techniques, and artificial intelligence computational methodologies. Future research efforts should focus on overcoming current technical challenges, including the creation of cost-effective spatial omics, advancing mechanistic studies—especially those pertaining to interactions within the immune microenvironment, and promoting clinical translation through interdisciplinary collaboration. The overarching goal is to develop targeted intervention strategies that specifically address the oncogenic network linked to DDX27.

Conclusion

DDX27, classified within the DEAD-box RNA helicase family, has been recognized as a pivotal regulator of RNA metabolism and a significant factor in tumorigenesis across various types of cancer. This review aims to synthesize the current understanding of the structural and functional characteristics of DDX27, emphasizing its multifaceted roles in cancer biology. DDX27 is acknowledged as a complex oncogenic driver with substantial potential for application in cancer diagnostics, prognostics, and therapeutic interventions. Future research endeavors should focus on elucidating its specific molecular mechanisms, regulatory networks within the context of cancer, and its feasibility, thereby aiding in the development of more effective therapeutic strategies for cancer treatment.

Abbreviations

GC

Gastric cancer

CRC

Colorectal cancer

BC

Breast cancer

HCC

Hepatocellular carcinoma

OSCC

Oral squamous cell carcinoma

MVP

Major vault protein

NPM1

Nucleophosmin 1

CIN

Chromosomal instability

CAS/CSE1L

Cellular apoptosis susceptibility protein

LPP

Lipoma-preferred partner

CAN

Copy number alteration

MiRNAs

MicroRNAs

EMT

Epithelial-mesenchymal transition

CSS

Cancer-specific survival

OS

Overall survival

RFS

Relapse-free survival

DFS

Disease-free survival

5-FU

5-Fluorouracil

SL

Synthetic lethality

SDL

Synthetic dosage lethality

cryo-EM

Cryo-electron microscopy

GANs

Generative adversarial networks

AI

Artificial intelligence

TAMs

Tumor-associated macrophages

PDO

Patient-derived organoid

Author contributions

Le Yang and Li Jun Yang conceived the topic and drew up the outline. Le Yang wrote and revised the original draft. Simon Wing-Fai Mok, Io Nam Wong, Hua Hui Li and Li jun Yang reviewed and edited the draft. All authors read and approved the final manuscript.

Funding

This work was supported Hunan University of Chinese Medicine Hospital-University Collaborative Fund (2024XYLH276) and the Macao Science and Technology Development Fund (Nos. 0133/2024/RIA2 and 0037/2022/ITP).

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Competing interests

The authors declare that there are no conflict of interest related to this publication.