The role of the transcription factor PATZ1 in tumorigenesis and metabolic regulation

Abstract

PATZ1 (POZ/BTB and AT hook containing zinc finger 1) is an important member of the POZ/BTB (Poxvirus and Zinc finger / Broad-complex, Tramtrack, and Bric-à-brac) family and has been confirmed to be involved in the development and progression of various tumors. Moreover, differential expression of PATZ1 is associated with the prognosis of multiple cancers and systemic metabolic patterns. It participates in the regulation of oncogenes and a range of biological processes, including glucose and lipid metabolism. This review aims to summarize the current understanding of the relationship between the transcription factor PATZ1, tumorigenesis, and metabolism, with the goal of providing a theoretical basis for the development of PATZ1-targeted therapies.

Introduction

Tumorigenesis and metabolic dysregulation have become two major factors threatening human health. Tumorigenesis is a complex process in which normal cells transform into cancer cells, often accompanied by genetic mutations or epigenetic alterations(Zhang et al. 2024). Metabolic dysregulation, particularly in lipid metabolism, glucose metabolism, and immune system balance, is increasingly recognized as a critical foundation for the initiation and progression of various cancers(Liberti and Locasale 2016) (O’Neill et al. 2016) (Röhrig and Schulze 2016). Transcription factors play pivotal roles in these processes by modulating the expression of target proteins and influencing cellular functions. PATZ1 has been identified as a potential prognostic biomarker in multiple cancers and metabolic conditions, with its expression closely associated with patients’ overall survival (OS) and disease-free survival (DFS). This review summarizes recent advances in understanding the roles of PATZ1 in tumor regulation, lipid metabolism, and immune modulation.

Molecular structure and function of TFs and the POZ/BTB family

Transcription factors (TFs) are a class of DNA-binding proteins that regulate gene expression by specifically promoting or repressing the transcription of target genes, thereby playing a pivotal role in the gene transcription process(Lambert et al. 2018).In addition, TFs can sense changes in intra- and extracellular signals to alter their own activity and affect gene activity.

More than 1,600 TFs are known to exist in the human genome, and some of these overactivated TFs can lead to the proliferation and migration of cancer cells(Peng et al. 2021). Some TFs have dual regulatory functions, acting as either transcriptional activators or repressors in cellular biological processes(King and Cidlowski 1998; Mitra 2020) (e.g., c-Myb and p53). c-Myb is not only associated with cellular proliferation and growth but also participates in the regulation of epigenetic processes in vivo. p53 suppresses tumorigenesis by regulating the cell cycle and inducing apoptosis(Alsayed et al. 2023). A complex interplay exists between the two, which may contribute to mechanisms by which tumor cells evade apoptosis(Ahmadi et al. 2021). Studies have shown that oncogenic super-enhancers (SEs) can activate the MAPK signaling pathway to promote malignant phenotypes of tumor cells, while these signaling pathways drive cancer progression by modulating the expression and activity of TFs(Jia et al. 2020).

The POZ/BTB (Poxvirus and Zinc finger / Broad-complex, Tramtrack, and Bric-à-brac) family represents a group of transcription factors with diverse functions, playing critical roles in cellular differentiation, proliferation, apoptosis, and tumorigenesis(Chaharbakhshi and Jemc 2016). The members of this family can be broadly classified into two categories. One category contains only the N-terminal POZ/BTB domain, which primarily mediates protein-protein interactions to recruit co-repressors (such as HDACs), alter chromatin structure, and inhibit gene expression(Costoya 2007); it also mediates protein dimerization or oligomerization to form transcription complexes, regulating cell proliferation, differentiation, and apoptosis. For example, KEAP1 is a classic oxidative stress-responsive regulatory factor that maintains cellular redox homeostasis by regulating the NRF2 signaling pathway(Yamamoto et al. 2018). NAC1, on the other hand, primarily participates in the maintenance of tumor stemness and cell migration. Studies have demonstrated that NAC1 enhances the migratory ability of ovarian cancer cells by regulating the cytoskeleton and pseudopod formation(Ren et al. 2022) (Dong et al. 2023). The other category consists of proteins containing both the N-terminal POZ/BTB domain and the C-terminal C2H2 zinc finger (ZF) structure, which are involved in cell growth and development, gene transcription, and immune regulation(Zhao et al. 2023). The most well-known example is BCL6, which promotes tumor cell proliferation and survival by inhibiting p53 activity, especially in certain types of B-cell lymphomas (such as diffuse large B-cell lymphoma (DLBCL), where it exerts a negative regulatory effect on p53(Huang and Melnick 2015). In summary, due to their unique structural features and integrative regulatory functions, POZ/BTB transcription factors have become important subjects of interest in transcriptional network research and targeted disease intervention strategies(Patalano et al. 2025).

Molecular structure and function of PATZ1 (Fig. 1)

Fig. 1.

Schematic structure of PATZ1

As a transcriptional regulator, PATZ1 can function as either a transcriptional activator or repressor depending on the cellular context, regulating gene expression(Fedele et al. 2000; Kobayashi et al. 2000). In 2000, PATZ1 was first identified as a novel member of the BTB/POZ family, and its role in transcriptional regulation has since been characterized(Fedele et al. 2017). The PATZ1 gene is located on human chromosome 22q12 and comprises six exons, producing four alternatively spliced transcript variants ranging from 3021 bp (short isoform) to 3812 bp (long isoform) (Shimamoto and Fujiwara 1968). Structurally, all protein variants contain a POZ/BTB structural domain at the N-terminus and a unique AT-hook DNA-binding motif (present only in PATZ1/PATZ2 among POZ/BTB proteins) located before the first zinc finger domain(Barakat et al. 2024). This motif consists of a conserved core sequence, GRP (glycine–arginine–proline), which recognizes adenine- and thymine-rich (AT-rich) regions of DNA. PATZ1 binds to the minor groove of DNA through its AT-hook(Aravind and Landsman 1998), thereby enhancing its transcriptional regulatory activity and participating in chromatin remodeling(Aravind and Landsman 1998). The C-terminal region contains a classical C2H2-type zinc finger structure (4–6 C2H2 ZFs depending on the splice variant). These repeats include two conserved pairs of cysteine and histidine residues coordinated by a single zinc ion, forming a well-characterized DNA/RNA-binding domain. This domain can adapt in a tandem arrangement to recognize nucleic acid sequences of varying lengths with high DNA-binding specificity(Piepoli et al. 2020). Due to the tissue/cell specificity of PATZ1, differences in interacting proteins, as well as varying p53 status and expression levels, it can act not only as a tumor suppressor gene but also as an oncogene, involved in the growth and migration of tumor cells(Valentino et al. 2013).

Dual roles of PATZ1 in tumours

Due to its structural specificity, PATZ1 exhibits dual regulatory functions (Table 1). In colorectal cancer (CRC), PATZ1 has been identified as an oncogenic regulator of gene expression. Elevated PATZ1 mRNA expression is observed in approximately 53% of CRC samples, and overexpression of PATZ1 has been shown to accelerate cell cycle progression. This effect may mimic that of the oncogene c-Myc, leading to an increased proportion of cells in the S phase and a reduction in G0/G1 phase cells, thereby promoting tumor cell proliferation(Tian et al. 2008). Research has shown that PATZ1 can prevent p53 from binding to its target gene promoter DNA. PATZ1, through its C-terminal zinc finger domain, forms a complex with p53, preventing the complex from binding to the promoters of downstream tumor suppressor genes (p21, PUMA, Gadd45). Additionally, PATZ1 itself can recognize certain p53 DNA recognition elements, competing for binding sites with p53, thereby accelerating the cell cycle, reducing apoptosis, and enhancing the malignant proliferative capacity of the cells(Keskin et al. 2015; Valentino et al. 2013).

Table 1.

Mechanism of action of PATZ1 in different cells

Biological environment	Promotion / Inhibition	Mechanism
colorectal cancer	Oncogenic	Overexpression of PATZ1 leads to a decreased proportion of cells in the G0/G1 phase and an increased proportion in the S phase, indicating accelerated entry into the DNA synthesis phase.
Thymus	Oncogenic	PATZ1 binds to p53 and prevents the activation of downstream target genes, thereby attenuating p53 function and promoting cell proliferation and survival.
thyroid cancer	Tumor-suppressive	Loss of PATZ1 leads to decreased expression of p53 target genes, enhanced EMT, and increased cell migration and invasiveness.
Glioblastoma multiforme	Tumor-suppressive	PATZ1 suppresses PUMA expression, thereby inhibiting the mitochondrial apoptotic pathway.

In thyroid cancer (TC), PATZ1 acts as a tumor suppressor. It is significantly underexpressed in pathological tissues. Under physiological conditions, PATZ1 is predominantly localized in the nucleus; however, in TC—particularly in aggressive undifferentiated carcinomas (ATCs)—PATZ1 is progressively mislocalized from the nucleus to the cytoplasm, or even completely excluded from the nucleus, resulting in the loss of its transcriptional regulatory function. Restoration of PATZ1 expression in thyroid cancer cell lines has been shown to reduce cell proliferation, migration, and invasion. EMT, a central mechanism in tissue remodeling, repair, and cancer progression, plays a key role in tumor development and metastasis(Lamouille et al. 2014). PATZ1’s ectopic expression in TC activates the p53 pathway, intervening in the regulation mechanisms of cytoskeletal remodeling, cell adhesion, and migration, thereby inhibiting the EMT process and the invasive potential of tumor cells. This inhibitory effect of PATZ1 is more pronounced in the presence of functional p53 but may also be mediated by its direct transcriptional regulation of EMT-related gene promoters independently of p53(Chiappetta et al. 2015). Furthermore, PATZ1 has also demonstrated tumor-suppressive properties in non-small cell lung cancer (NSCLC). Overexpression of PATZ1 in NSCLC cells significantly inhibits cell proliferation, migration, and invasion. Immunohistochemical (IHC) analysis of 104 NSCLC tissue samples revealed that tumors with high PATZ1 expression (≥ 70%) exhibited a markedly lower proportion of PD-L1 (programmed death-ligand 1) positivity compared to those with low expression (12.5% vs. 53%). In vivo studies showed that PATZ1-knockout mice developed proliferative lesions and adenocarcinoma-like structures in lung tissue, accompanied by increased PD-L1 expression, upregulation of epithelial–mesenchymal transition (EMT) markers (e.g., N-cadherin and Vimentin), and downregulation of E-cadherin. These findings suggest that PATZ1 may indirectly suppress PD-L1 expression by inhibiting EMT progression. However, the study primarily focused on the phenotypic changes in EMT and PD-L1 expression, lacking in-depth mechanistic investigations(Lucà et al. 2023). PUMA (p53 upregulated modulator of apoptosis), a pro-apoptotic Bcl-2 family member upregulated by p53, plays a critical role in mitochondrial apoptosis initiation. Immunofluorescence confocal microscopy has revealed that PATZ1 co-localizes with PUMA in the nucleus, indicating a potential direct or indirect interaction. This association enhances PUMA expression and subsequently increases the transcription of apoptosis-related genes, including PARP1, Caspase-3, and PUMA itself, thereby promoting apoptosis and inhibiting tumor growth(Tao et al. 2022).

Gene fusion involving PATZ1

Numerous studies have shown that PATZ1 can undergo chromosomal rearrangement through gene fusion. Gene fusion refers to the interconnection of two distinct genes, or portions thereof, via chromosomal rearrangement, including translocation, insertion, or deletion, leading to the generation of novel fusion genes that encode new proteins and drive distinct biological traits(Glenfield and Innan 2021; Wang et al. 2021b). EWSR1, encoding an RNA-binding protein, is implicated in the pathogenesis of various soft tissue sarcomas, such as Ewing sarcoma (EWS). The EWSR1 gene is well known for forming gene fusions with multiple partners(Schoolmeester et al. 2021) (Antonescu et al. 2010) (Benini et al. 2020). The EWSR1–PATZ1 fusion gene has been frequently identified in glioneuronal tumors (GNTs). The formation of this fusion may result from the proximity of the two genes—separated by only ~ 20 Mb on the chromosome—and their opposite transcriptional orientations, which may promote chromosomal translocation or copy number variation, thereby fusing the 5′ end of EWSR1 with the 3′ end of PATZ1(Bridge et al. 2019). Studies using FISH analysis revealed that approximately 25% of BRAFV600E-positive samples exhibited EWSR1 break-apart signals, suggesting a potential EWSR1–PATZ1 fusion. The fusion point in PATZ1 typically occurs in the middle of exon 1 rather than at canonical splice junctions, preserving the C-terminal C2H2 zinc finger domain of PATZ1(Alhalabi et al. 2021). Conversely, the EWSR1 fusion breakpoint commonly lies between exons 8 and 9, resulting in a chimeric gene that loses the tumor-suppressive functions of PATZ1 while gaining the transcriptional activation domain of EWSR1. This creates a novel transcriptional regulator with aberrant regulatory activity(Siegfried et al. 2019). Tumors with EWSR1-PATZ1 fusion are often associated with TERTp mutations (one of the key factors leading to enhanced telomerase activity in tumor cells), particularly in certain high-grade neuroepithelial tumors, where they act synergistically to enhance tumor proliferation, leading to sustained tumor cell growth and survival(Kim et al. 2023). At the same time, this fusion may influence the expression of genes such as PAX2, GATA2, and IGF2, affecting pathways involved in the proliferation of neural stem cells, tumor stem cell function, and immune evasion, thereby driving tumor malignancy and making it more invasive and resistant to treatment(Alhalabi et al. 2021). The EWSR1-PATZ1 gene fusion is considered a characteristic molecular marker in multiple tumor types, suggesting that it may represent a novel tumor type, although it has not yet been officially included in the WHO classification (Tauziède-Espariat et al. 2025). Moreover, have also been observed in a subset of pediatric central nervous system (CNS) tumors(Burel-Vandenbos et al. 2020; Chadda et al. 2021; Michal et al. 2021; Rossi et al. 2021; Stichel et al. 2019). These tumors exhibit atypical glial, ependymal, or glioneuronal morphology, and PATZ1 expression levels are markedly higher in CNS tumors than in other low-grade gliomas in children. However, the molecular mechanisms underlying these phenomena remain to be fully elucidated(Alhalabi et al. 2021).

PATZ1 in the maintenance of stemness and glycolytic metabolism (Fig. 2)

Fig. 2.

Metabolic Mechanisms Involving PATZ1

Human embryonic stem cells (hESCs) are pluripotent cells derived from early human embryos, capable of unlimited self-renewal and differentiation into nearly all somatic cell types(Avior et al. 2016). The maintenance of pluripotency in hESCs requires a precise transcriptional network. ChIP-seq analysis revealed that OCT4 and NANOG binding peaks were significantly enriched at the promoter region and first intron of the PATZ1 gene, suggesting that they may function as upstream transcriptional regulators of PATZ1. Moreover, luciferase reporter assays further demonstrated that PATZ1 can activate the promoters of OCT4 and NANOG, indicating the existence of a positive feedback loop in which OCT4 and NANOG activate PATZ1, which in turn enhances their expression, thereby maintaining stemness stability(Ow et al. 2014). At both the RNA and protein levels, PATZ1 is highly expressed in undifferentiated hESCs and is downregulated upon differentiation. Loss of PATZ1 expression induces spontaneous differentiation of hESCs toward mesodermal (e.g., MYF6, NKX2.5, FGF5) and endodermal (e.g., FOXA1, FOXA2, GATA6, SOX17) lineages, disrupts the pluripotency network, and promotes lineage-specific gene expression, highlighting PATZ1 as a key transcription factor required for maintaining pluripotency in hESCs(Huang et al. 2024). Beyond human ESCs, PATZ1 also plays a crucial role in maintaining pluripotency in mouse embryonic stem cells (mESCs). Upon PATZ1 knockdown, cells display flattened morphology, blurred colony boundaries, and reduced alkaline phosphatase (AP) staining. In Patz1 heterozygous knockout (Patz1⁺/⁻) mouse embryonic fibroblasts (MEFs), levels of active histone marks such as H3K4me2, H3K4me3, and H3K36me3 are increased, while repressive marks such as H3K9me3 and HP1α are significantly reduced. This epigenetic profile reflects a globally open chromatin state, conducive to the activation of the pluripotency transcriptional network(Ma et al. 2014).

Embryonic stem cells (ESCs) primarily rely on oxidative phosphorylation (OXPHOS) in a quiescent state, but shift to glycolysis upon activation and differentiation(Intlekofer and Finley 2019). In this study, loss of PATZ1 led to a ~ 40% reduction in mitochondrial oxygen consumption rate (OCR) and an approximately 20% decrease in glycolysis-derived ATP production. Interestingly, levels of glycolysis-related metabolites—including glutamine, glutamate, glucose, and serine—were significantly increased. Furthermore, ChIP-seq analysis revealed that PATZ1 was significantly enriched at the regulatory regions of key glycolytic enzymes, especially PFKP (enrichment fold = 10.35) and PKM (enrichment fold = 4.51), which encode phosphofructokinase and pyruvate kinase, the rate-limiting and terminal enzymes of the glycolytic pathway, respectively(Wang et al. 2021a) (Li et al. 2021). RNA-seq data also revealed that in hESCs lacking PATZ1, the expression of multiple metabolism-related genes was downregulated, accompanied by alterations in cell fate decisions. These findings collectively underscore the central role of PATZ1 in maintaining metabolic activity(Huang et al. 2024). Research has also shown that PATZ1 has a dose-dependent effect during cell reprogramming, with its expression level directly influencing reprogramming efficiency. Overexpression of PATZ1 activates the Ink4a/Arf locus (an important gene region regulating cell senescence and tumor suppression), leading to the upregulation of p16 and p53, which induces cell senescence and suppresses reprogramming. When the expression of PATZ1 is reduced (through ectopic knockout or partial deletion), reprogramming efficiency is significantly improved. Notably, PATZ1+/− MEFs show higher reprogramming efficiency compared to PATZ1+/+ MEFs, whereas PATZ1−/− MEFs exhibit the lowest reprogramming efficiency. The specific regulatory mechanism may be related to cell senescence and epigenetic regulation. Additionally, PATZ1 inhibits reprogramming by suppressing the transcription of c-Myc. PATZ1 binds to the intronic region of the c-Myc gene, inhibiting its expression, which in turn affects reprogramming efficiency(Ma et al. 2014). CXCR4 is a key regulator driving the transformation of gliomas into a mesenchymal phenotype by enhancing migratory and invasive capabilities(Zhu et al. 2013). In glioblastoma stem cells (GSCs), PATZ1 expression is significantly inversely correlated with CXCR4. Reduced PATZ1 expression leads to CXCR4 upregulation, which promotes EMT, thereby enhancing invasiveness and conferring drug resistance to cancer cells(Guadagno et al. 2017). In contrast, PATZ1 is markedly upregulated in GSCs, and its expression shows a positive correlation with classical stemness markers (CD133, Nestin, SOX2, OCT4), while displaying a negative correlation with mesenchymal markers such as CD44, CXCR4, ZEB1, and STAT3. These findings highlight the essential role of PATZ1 in preserving the stem-like state of GSCs and in inhibiting their transition to a mesenchymal and invasive phenotype.

PATZ1 in lipid metabolism

Adipose tissue (AT) is an essential connective tissue in the human body that plays a critical role in energy storage, endocrine regulation, and the maintenance of body temperature(Zwick et al. 2018). Evidence from ChIP-seq data indicates that PATZ1 binds to the regulatory regions of lipid metabolism–related enzymes, including ELOVL5 (enrichment fold = 4.49) and PTGR1 (enrichment fold = 4.52) (Huang et al. 2024).Moreover, cooperates with the transcription factor C/EBPβ, co-occupying the promoter regions of adipogenesis-related genes, thereby participating in transcriptional regulation. Their binding peaks overlap at the promoters of several key adipogenic genes(Oishi et al. 2005). As a structural transcription factor, PATZ1 also interacts with GTF2I through protein–protein interactions, forming a complex that binds to and regulates promoters of fat development genes such as Myc, Igf1r, and Pvt1. ChIP-seq analysis further revealed that PATZ1 binding was most prominent at Day 0 (initiation of adipogenic differentiation), but was nearly absent by Day 5 (differentiation midpoint), suggesting a sentinel-like role during the early phase of adipogenesis. Loss of PATZ1 impairs the expression of these initiating transcription factors, thereby disrupting adipocyte fate determination and blocking adipogenesis(Patel et al. 2024). FABP4 (fatty acid-binding protein 4) is a critical mediator of lipid metabolism and angiogenesis(Herroon et al. 2013) (Prentice et al. 2019). PATZ1 was shown to bind the promoter region of FABP4 (− 1355 to − 1247 bp), thereby affecting its transcriptional activity. In high-glucose cellular models, PATZ1 expression is markedly upregulated, leading to persistent suppression of FABP4, which disrupts fatty acid metabolism and energy flux, ultimately attenuating angiogenic signaling. In vivo experiments further demonstrated that overexpression of PATZ1 in human endothelial colony-forming cells (ECFCs) significantly impaired angiogenesis in a murine Matrigel plug model, as evidenced by decreased vascular density assessed by CD31 immunohistochemistry, indicating that PATZ1 suppresses angiogenic capacity in vivo, with FABP4 acting as a critical downstream effector(Chen et al. 2016). FADS1 (fatty acid desaturase 1), a key enzyme in the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs), is also targeted by PATZ1. It encodes delta-5 desaturase (D5D), the rate-limiting enzyme converting precursors into LC-PUFAs(Nakamura and Nara 2004). PATZ1 directly binds to the rs174557 site within intron 1 of FADS1, repressing its expression, thereby reducing D5D activity and modulating LC-PUFA biosynthesis. Notably, PATZ1 regulation at rs174557 is allele-specific: the D allele, carrying a G > A mutation, disrupts the PATZ1 binding motif, resulting in reduced PATZ1 affinity, increased FADS1 expression, and elevated levels of pro-inflammatory mediators such as arachidonic acid, prostaglandins, and leukotrienes. This aberrant fatty acid metabolism may contribute to chronic inflammation, potentially increasing the risk of inflammatory diseases, including colorectal cancer, rheumatoid arthritis, and inflammatory bowel disease. This study uncovers a novel mechanism by which PATZ1 regulates fatty acid metabolism, providing molecular insight into its role in metabolic adaptability(Pan et al. 2017). Increasing evidence suggests that metabolic crosstalk exists between adipose tissue and tumors. Lipid metabolic reprogramming has emerged as a key mechanism of tumor metabolic adaptation, offering new insights into the interplay between the tumor microenvironment and metabolic networks(Beloribi-Djefaflia et al. 2016) (Jin et al. 2023). Although no current studies directly link PATZ1 to tumor lipid metabolism, its regulation of key adipogenic transcription factors such as C/EBPα and PPARγ during adipocyte differentiation suggests a potential role in tumor metabolic reprogramming(Patel et al. 2024). Future investigations integrating ChIP-seq, ATAC-seq, and metabolomics in tumor tissues are warranted to elucidate whether PATZ1 contributes to tumor metabolic adaptation via transcriptional control of lipid metabolic genes or chromatin remodeling.

PATZ1 in immune metabolism

The metabolic regulatory function of PATZ1 may influence tumor progression by modulating immune cell behavior. Ivan Bilic et al. found that PATZ1 is highly expressed in double-negative (DN) thymocytes, but its expression is markedly downregulated in double-positive (DP) and CD8 single-positive (SP) thymocytes. At the DN stage, PATZ1 interacts with the nuclear receptor corepressor complex (N-CoR) through its N-terminal POZ/BTB domain and binds to the CD8 enhancer E8II region, thereby recruiting histone deacetylases to repress the transcription of CD8a/CD8b1 (epigenetic silencing), ultimately suppressing CD8 expression(Bilic et al. 2006). Shinya Sakaguchi et al. also demonstrated that PATZ1 binds to enhancer regions of the CD8 gene (E8I and E8II) to inhibit CD8 expression. However, at the DP stage, although PATZ1 deficiency leads to increased CD8 expression, this expression remains incomplete, suggesting that PATZ1 maintains the CD8 promoter in a “silent” state during the DN-to-DP transition to regulate lineage commitment. Concomitantly, loss of PATZ1 increases the proportion of CD4⁺ T cells, disrupting the CD4:CD8 ratio and misdirecting some CD8⁺ T cell precursors toward the CD4⁺ lineage. Moreover, in PATZ1-deficient DP cells, expression of ThPOK—a key transcription factor driving CD4⁺ T cell differentiation—is significantly upregulated (due to release of repression), causing a subset of MHC-I–restricted T cells to aberrantly adopt a CD4-like phenotype(Sakaguchi et al. 2010). Further studies have shown that PATZ1 plays a critical role in the lineage specification of invariant natural killer T (iNKT) cells(Look et al. 2023).PATZ1 is expressed in iNKT cells, with higher levels observed in the iNKT2 subset compared to iNKT1 and iNKT17. In PATZ1-knockout mice, the proportion of iNKT2 cells is significantly increased, while iNKT1 and iNKT17 subsets are reduced. This alteration may result from the upregulation of Egr2 (a positive regulator of iNKT lineage differentiation) and ThPOK expression caused by the loss of PATZ1(Orola et al. 2019). In CD8⁺ T cell differentiation, PATZ1 and Runx3 exhibit a complex interplay of synergy and antagonism. During the differentiation of cytotoxic T lymphocytes (CTLs), PATZ1 cooperates with Runx3 to regulate the expression of critical effector molecules such as CD8α, granzyme B, and perforin(Cruz-Guilloty et al. 2009). Notably, PATZ1 deficiency can partially compensate for the Runx3-dependent transcriptional program in Runx3-deficient settings, thus preserving CTL effector function. In contrast, during memory T cell formation, PATZ1 and Runx3 exhibit opposing regulatory roles: Runx3 promotes the generation of terminal effector (TE) and memory precursor (MP) cells, whereas PATZ1 deficiency enhances MP formation while suppressing TE differentiation. These findings suggest a stage-specific regulatory mechanism of the PATZ1/Runx3 axis in maintaining CD8⁺ T cell lineage integrity, effector function, and memory formation(Gülich et al. 2021). Additionally, PATZ1 affects the differentiation of regulatory T cells (FOXP3⁺ Tregs), which are essential for immune tolerance and homeostasis. In PATZ1-knockout mice, the proportion of Treg cells is increased. During thymic Treg development, PATZ1 expression gradually declines, and its deficiency—while not altering the epigenetic landscape of the Foxp3 promoter or its conserved noncoding sequence (CNS) regions—leads to enhanced Foxp3 expression. This suggests that PATZ1 downregulation may be a critical step in Treg differentiation(Andersen et al. 2019). PD-L1, a known immunosuppressive molecule(Peper-Gabriel et al. 2022). Overexpression of PATZ1 significantly reduces PD-L1 mRNA and protein levels, further supporting its role in modulating immune system activity through PD-L1 suppression(Lucà et al. 2023). A study utilizing the GEO database also supports the association between PATZ1 and immune-related diseases. Regulatory Impact Factor (RIF) analysis ranked PATZ1 among the top TFs implicated in osteoarthritis (RIF = 89,107.36442), although the precise regulatory mechanisms remain to be elucidated(Li et al. 2013).

Signaling pathways involving PATZ1

Recent studies have revealed that PATZ1 is not only involved in regulating key tumor-associated signaling pathways, such as Ras–MAPK–ERK, WNT, and PI3K/AKT, but may also serve as a cross-talk node coordinating multiple pathways synergistically. The Ras–MAPK–ERK and WNT pathways are well known for their roles in promoting tumor proliferation and migration, often being aberrantly activated in cancer. PATZ1 binds to the promoter regions of p-ERK1/2–related genes, suppressing their phosphorylation and activation, thereby attenuating the amplification of proliferative signals. Furthermore, as a co-regulator of p53, PATZ1 enhances p53-mediated cell cycle arrest and apoptosis. Knockdown of PATZ1 leads to reduced expression of p53-target genes, consequently promoting tumor cell proliferation and migration. These findings suggest that PATZ1 modulates the Ras/MAPK/ERK pathway through both p-ERK1/2 inhibition and p53 regulation(Kobayashi et al. 2000). SMURF1, an E3 ubiquitin ligase, directly interacts with PATZ1 in the WNT signaling pathway, facilitating its ubiquitination and degradation, which leads to a significant reduction in CCNG2 (a cyclin G2 protein). This, in turn, relieves CCNG2-mediated repression of WNT signaling and enhances pathway activation(Chen et al. 2025). NSCLC, PATZ1 also participates in WNT signaling regulation. Specifically, PATZ1 binds directly to the PD-L1 promoter, suppressing its transcription. In PATZ1-knockdown NSCLC cells, PD-L1 expression is upregulated and WNT pathway activity is enhanced, suggesting that PATZ1 mediates co-regulation of the immune microenvironment and WNT signaling(Lucà et al. 2023). In hepatocellular carcinoma (HCC), RRP15 (ribosomal RNA processing protein 15) enhances PATZ1 transcriptional activation, promoting its binding to the LAMC2 promoter, resulting in LAMC2 upregulation, which triggers FAK autophosphorylation and subsequent activation of both PI3K/AKT and MAPK pathways, thereby promoting HCC cell migration(Pan et al. 2024). Moreover, PATZ1 also regulates gene expression through epigenetic mechanisms such as DNA methylation. In PATZ1-overexpressing cells, the repressive histone modification H3K27me3 is enriched at the Ink4a/Arf promoter, leading to inactivation of the Ink4a/Arf axis and enhanced cell proliferation. Conversely, in PATZ1-deficient cells, H3K4me3, an activating histone mark, is highly enriched at the same promoter region, activating Ink4a/Arf expression and inducing cell cycle arrest and senescence(Ma et al. 2014).In summary, PATZ1 exerts central regulatory functions in multiple signaling and epigenetic pathways. Its role as a multi-pathway integrator and transcriptional coordinator merits further investigation.

Clinical therapeutic potential and targeted therapy of PATZ1

As a structurally unique member of the POZ/BTB TF family, PATZ1 has demonstrated significant prognostic value in various solid and hematologic malignancies. In patients with glioblastoma of the neuroblastic subtype, those with high PATZ1 expression exhibited a median overall survival of 53 months, compared to only 10 months in patients with low expression. Cox regression analysis further confirmed that low PATZ1 expression serves as an independent predictor of poor prognosis(Guadagno et al. 2017). In TC, PATZ1 expression progressively decreases during the transition from differentiated to undifferentiated subtypes, suggesting that PATZ1 could serve as a potential biomarker for assessing thyroid cancer differentiation status(Lamouille et al. 2014). In patients with diffuse large B-cell lymphoma (DLBCL), low PATZ1 expression was associated with a poorer prognosis following R-CHOP immunochemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). This suggests that PATZ1 expression is significantly correlated with both OS and DFS(Franco et al. 2016).In cases harboring the EWSR1–PATZ1 fusion gene, approximately 70% of patients achieved DFS postoperatively, and around 20% remained disease-free for at least two years after surgery. These tumors generally exhibited low metastatic potential, although a subset of patients developed distant metastases following local progression. Compared to conventional EWS, tumors harboring the EWSR1–PATZ1 fusion gene tend to show slower progression and demonstrate better therapeutic responsiveness(Yagi et al. 2024). Furthermore, doxorubicin-induced DNA damage has been shown to trigger degradation of the PATZ1 protein, thereby relieving its inhibitory effect on p53. This mechanism plays a crucial role in modulating doxorubicin sensitivity, suggesting that PATZ1 may represent a potential therapeutic target for clinical intervention(Keskin et al. 2015). Additionally, a network-based drug screening platform (BREEZE) was employed to identify candidate compounds based on tumor molecular characteristics. Several agents—including paclitaxel, D-actinomycin, volasertib (a PLK1 inhibitor), navitoclax (a BCL-2/BCL-XL/BCL-w inhibitor), and I-BET-151 (a bromodomain inhibitor)—showed therapeutic potential against EWSR1–PATZ1 fusion–driven tumors. However, their efficacy requires further validation through preclinical studies and clinical trials(Kim et al. 2023).

The development of small molecule inhibitors or interfering RNA technology that interferes with the binding of TFs to target DNA can effectively inhibit the activity of oncogenic TFs, thereby achieving better outcomes in cancer therapy(Zhou et al. 2024). CRISPR-Cas9 technology enables targeted cleavage and editing of specific DNA sequences. This technology can be used to cut and edit TFs in order to achieve the goal of gene therapy(Knott and Doudna 2018). Waisse Waisi and colleagues proposed that inhibition of ataxia telangiectasia and Rad3-related (ATR) could replicate replication stress, offering a novel therapeutic target for CIC-rearranged sarcomas. Inhibition of ATR slows tumour growth and increases the sensitivity of CIC-rearranged sarcomas to radiotherapy(Cripe et al. 2024). However, the therapeutic potential of PATZ1 in rearranged sarcomas still requires further large-scale validation. Carbon ion radiotherapy (CIRT) is an advanced high-energy particle therapy that has been applied to the treatment of inoperable or locally recurrent tumors(Sudo et al. 2024). A recent case report described a patient harboring the EWSR1–PATZ1 fusion gene who received CIRT. The patient exhibited no significant tumor progression or adverse events within 13 months, indicating that CIRT may be a promising approach for controlling local tumor progression in fusion gene–driven tumors(Yagi et al. 2024). Given that PATZ1 is involved in the regulation of pathways associated with PD-L1 expression and the tumor immune microenvironment, its expression status may influence the therapeutic efficacy of PD-L1/4-1BB bispecific antibodies(Mao et al. 2024; Peper-Gabriel et al. 2022). Metabolic interventions (e.g., blocking lactate production, modulating glutamine metabolism, regulating lipid metabolism pathways, etc.) can reverse the state of immunosuppression, enhance T-cell activity, and boost the response rate to immunotherapies such as PD-1/PD-L1 inhibitors(Pauken et al. 2021).Although immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway have significantly improved the prognosis of patients with advanced NSCLC, only a subset of patients responds to this form of therapy. PATZ1 expression is negatively correlated with PD-L1, suggesting that it may influence the efficacy of PD-1/PD-L1–based immunotherapy. Patients with high PATZ1 expression exhibit a median progression-free survival (PFS) of 5 months, significantly shorter than the 15.7 months observed in patients with low PATZ1 expression. Collectively, these findings indicate that PATZ1 may serve not only as a prognostic biomarker for NSCLC, but also as a modulator of immunotherapy response(Lucà et al. 2023). In the future, therapeutic strategies that integrate PATZ1 expression profiling with metabolic modulation and immunotherapy may enable more personalized and precise cancer interventions. Although PATZ1 is involved in the development of many tumours, most of the research has focused on cellular models and phenotypes, and there are fewer in vivo knockout or overexpression animal models for deeper mechanisms. Moreover, the dual regulation of PATZ1 in different diseases has not yet been successfully investigated, limiting the clinical translation of PATZ1.

Summary and future perspectives

In conclusion, PATZ1, as a well-structured and multifunctional TF, plays a key role in stem cell maintenance, metabolic regulation, immune modulation, and tumourigenesis and development. Its function in tumours can be either as a typical oncogenic factor or pro-oncogenic in some types and this dual role depends on the cell type, the p53 status, and the localisation and expression level of the protein.

In recent years, with the rapid development of spatial multi-omics technologies (e.g., spatial transcriptome, spatial metabolome, and spatial proteome), the molecular heterogeneity and metabolic microenvironmental dynamics within tumours have been accurately resolved while preserving tissue structure information(Cao et al. 2024; Hu et al. 2024). Although studies have confirmed the important regulatory functions of PATZ1 in glycolysis, lipid metabolism, and immune metabolism, systematic investigations on its spatial expression characteristics and their association with local metabolic status remain limited. In the future, leveraging spatial genomics platforms may enable the integration of the spatial correlation between PATZ1 expression patterns and key metabolic pathways, as well as immune cell infiltration status, thereby constructing its regulatory network within the tumour metabolic microenvironment. This approach would not only help elucidate the mechanisms by which PATZ1 participates in tumour metabolic reprogramming and immune escape but also provide a theoretical and technical foundation for developing region-specific targeted intervention strategies.

Author contributions

Y.Z. conceived and designed the study, and wrote the manuscript. J.B.C. revised and edited the manuscript. C.S. reviewed and approved the final version. All authors reviewed and approved the final manuscript.

Funding

Innovation Project of Guangxi Graduate Education（No: YCSW2025249）and Clinical Research “Climbing” Program of the First Affiliated Hospital of Guangxi Medical University (No: YYZS2024018).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no conflict of interest.