PABPC1 in Cancer: From a Translational Housekeeper to a Stress‐Responsive Regulatory Hub

ABSTRACT

PABPC1, long recognized as a constitutive translational housekeeper, has emerged as a stress‐responsive translational reprogramming hub in cancer. This review synthesizes recent paradigm shifts that redefine PABPC1 function: From global translation maintenance to selective oncogenic mRNA amplification via liquid–liquid phase separation; from binary protein‐RNA interactions to complex regulatory networks involving lncRNAs and circRNAs that modulate PABPC1 stability, localization, and target selectivity; and from diffuse cytoplasmic distribution to functionally compartmentalized condensates. PABPC1 integrates diverse post‐translational modifications, including SUMOylation, acetylation, and ubiquitination, that enable stress adaptation, and actively regulates alternative polyadenylation to influence 3′UTR length and gene expression. Positioned at the convergence point of multiple oncogenic signaling pathways (PI3K/AKT, Wnt/β‐catenin, NF‐κB, and etc.), PABPC1 converts upstream signals into translational outputs that drive tumor progression, metastasis, and therapy resistance across malignancies. Its functional duality, context‐dependent activities, and paralog‐specific roles underscore both the complexity and therapeutic potential of targeting this multifaceted RNA‐binding protein.

PABPC1 shifts from a translational housekeeper to a stress‐responsive oncogenic hub via phase separation, PTMs, and non‐coding RNA crosstalk, selectively driving oncogene translation and therapy resistance in cancer.

Abbreviations

AKT

AKT serine/threonine kinase

APA

alternative polyadenylation

ARD1

arrest‐defective 1

C/EBPβ

CCAAT/enhancer‐binding protein beta

CARM1

coactivator associated arginine methyltransferase 1

ccRCC

clear cell renal cell carcinoma

circRNA

circular RNA

CML

chronic myeloid leukemia

DLG5

discs large homolog 5

eIF4G

eukaryotic translation initiation factor 4G

ELK3

ETS domain‐containing protein Elk‐3

EMT

epithelial‐mesenchymal transition

eRF3

eukaryotic release factor 3

FIP1L1

FIP1 like 1

GCLC

glutamate‐cysteine ligase catalytic subunit

HCC

hepatocellular carcinoma

hnRNPLL

hnRNP L‐Like protein

IDO1

indoleamine 2,3‐dioxygenase 1

IFI27

interferon alpha‐inducible protein 27

IGF2BP2

insulin‐like growth factor 2 mRNA‐binding protein 2

ILK

integrin‐linked kinase

JAK2

janus kinase 2

LARP1

La‐related protein 1

LLPS

liquid–liquid phase separation

lncRNA

long non‐coding RNA

METTL14

methyltransferase‐like 14

miRNA

microRNA

MK2

mitogen‐activated protein kinase‐activated protein kinase 2

MKRN3

makorin RING‐finger protein 3

MLLE

mademoiselle

NF‐κB

nuclear factor kappa B

NMD

nonsense‐mediated mRNA decay

NOTCH1

notch receptor 1

NRF2

nuclear factor erythroid 2‐related factor 2

NSCLC

non‐small cell lung cancer

NUMB

NUMB endocytic adaptor protein

PABPC1

poly(A)‐binding protein cytoplasmic 1

PABPC1L

poly(A)‐binding protein cytoplasmic 1‐like protein

PABPN1

poly(A)‐binding protein nuclear 1

PAIP1/2

PABP‐interacting protein 1/2

PAK1

p21‐activated kinase 1

PAM2

PABP‐interacting motif 2

PAN2/3

PABPC1‐dependent poly(A)‐specific ribonuclease subunit 2/3

PCF11

PCF11 cleavage and polyadenylation factor subunit

PGAM1

phosphoglycerate mutase 1

PGK1

phosphoglycerate kinase 1

PI3K

phosphoinositide 3‐kinase

PLCB1

phospholipase C beta 1

PTEN

phosphatase and tensin homolog

PTM

post‐translational modification

PUM1/2

Human pumilio homolog 1 and 2

R493me2a

asymmetric dimethylation of arginine 493

RAX2

retina and anterior neural fold homeobox 2

RBBP7

retinoblastoma‐binding protein 7

RBP

RNA‐binding protein

RRM

RNA recognition motif

SETDB1

SET domain bifurcated histone lysine methyltransferase 1

SG

stress granule

SLC27A5

solute carrier family 27 member 5 (also known as FATP5)

SOX9

SRY‐box transcription factor 9

SREBP1

sterol regulatory element‐binding protein 1

STAT1

signal transducer and activator of transcription 1

SUMOylation

small ubiquitin‐like modifierylation

SUZ12

zeste 12 homolog

TKI

tyrosine kinase inhibitor

TNBC

triple‐negative breast cancer

TOB1/2

transducer of ERBB2 1/2

TSC22D1

TSC22 domain family member 1

UBE2M

ubiquitin conjugating enzyme E2M

UBE4B

E3 ubiquitin ligase E4B

UPF1

UPF1 RNA helicase and ATPase

USP39

ubiquitin specific peptidase 39

UTR

untranslated region

Wnt

wingless‐type MMTV integration site family

1. Introduction

Poly(A)‐binding protein cytoplasmic 1 (PABPC1) is a highly conserved RNA binding protein ubiquitously expressed in eukaryotic cells [1]. Through binding to the poly(A) tail of mRNAs and interacting with the 5′ cap binding complex, PABPC1 promotes the formation of a closed loop mRNA conformation that stimulates translation initiation and protects transcripts from degradation [2, 3, 4, 5, 6, 7]. Consequently, PABPC1 has long been considered a constitutive translational housekeeper. However, accumulating evidence has revealed its far more versatile and context‐dependent roles in tumor biology.

PABPC1 is aberrantly overexpressed in a wide range of malignancies, including ovarian cancer, esophageal carcinoma, gastric cancer, nasopharyngeal carcinoma, and breast cancer [8, 9, 10, 11, 12, 13]. Unlike classical oncoproteins such as p53 or Ras, which directly modulate transcription or signaling cascades, PABPC1 operates primarily through post‐transcriptional regulatory networks—a property intrinsically linked to its structural domains: the RNA recognition motifs (RRMs) and the C‐terminal mademoiselle (MLLE) domain [4, 14, 15].

Over the past decade, three paradigm shifts have reshaped our view of PABPC1: from single target regulation to global translation reprogramming; from binary protein‐RNA interactions to complex networks involving long non‐coding RNAs (lncRNAs) and circular RNAs (circRNAs); and from diffuse cytoplasmic distribution to phase separation driven functional compartmentalization. In parallel, PABPC1 is subject to various post‐translational modifications (PTMs) that enable stress adaptation, and it actively regulates alternative polyadenylation (APA) to influence 3′ untranslated region (UTR) length. These advances collectively establish PABPC1 as a stress‐responsive translation reprogramming hub in cancer, challenging its traditional designation as a mere housekeeper.

2. PABPC1 Is a Central Node in Post Transcriptional Regulation

2.1. Classical Functions in Translation Control

PABPC1 consists of four N terminal RRMs (RRM1‐4), a proline rich disordered linker, and a C terminal MLLE domain [16, 17]. RRM1‐2 bind the poly(A) tail with high affinity, whereas RRM3‐4 recognize AU rich elements and other non poly(A) RNA sequences. Through its MLLE domain, PABPC1 recognizes the PABP interacting motif 2 (PAM2) and recruits a variety of effector proteins involved in translation regulation: PABP interacting protein 1/2 (PAIP1/2), mRNA degradation (PABPC1‐dependent poly(A)‐specific ribonuclease subunit 2/3 (PAN2/3), transducer of ERBB2 1/2 (TOB1/2)), the microRNA pathway (GW182), and translation termination: eukaryotic release factor 3 (eRF3) (Figure 1) [17, 18, 19, 20, 21, 22, 23].

FIGURE 1.

The PABPC1 domain structure together with its interacting partners.

The core function of PABPC1 is to interact with eukaryotic translation initiation factor 4G (eIF4G), thereby forming an mRNA closed loop that bridges the 3′ poly(A) tail and the 5′ cap [24, 25]. This conformation facilitates ribosome recycling and protects mRNA from exonucleolytic degradation [7, 24, 26, 27]. In this process, PAIP1 enhances PABPC1‐mediated translation initiation, whereas PAIP2 serves as a suppressor, together maintaining a finely tuned balance in translational control.

Beyond translation initiation, PABPC1 participates in multiple aspects of mRNA metabolism. Its interaction with GW182 is essential for microRNA induced silencing complex function [21]. PABPC1 binding to eRF3 acts to suppress nonsense‐mediated mRNA decay (NMD); however, the presence of a long 3′UTR relieves this PABPC1‐mediated suppression, thereby modulating whether oncogene transcripts escape NMD surveillance [28, 29, 30]. PABPC1 also contributes to translation coupled mRNA turnover, as exemplified by its involvement in the deadenylation and translational control network mediated by the coding region instability determinant of FOS proto oncogene mRNA [31, 32]. Furthermore, PABPC1 can bind the poly(A) tail of its own transcript, participating in pre‐mRNA splicing and autoregulating its own mRNA metabolism [33, 34].

Beyond its core partners, PABPC1 operates within a broader RNA‐binding protein (RBP) network through redundancy, competition, and cooperation. For example, functional redundancy is observed between PABPC1 and its paralog PABPC4 in pumilio‐mediated mRNA decay [25]; competitive interactions between PABPC1 and UPF1 RNA helicase and ATPase (UPF1) for binding to the translation termination complex modulate nonsense‐mediated mRNA decay [29]; and synergistic cooperation is exemplified by PABPC1 partnering with GW182 to facilitate microRNA (miRNA)‐mediated repression [21]. Collectively, these examples illustrate that PABPC1 functions as an integral node within a dynamic RBP landscape, where its activities are modulated through multi‐layered interplay: a perspective that adds mechanistic depth to its context‐dependent roles in tumor biology.

2.2. Dynamic Regulation by Post Translational Modifications

The activity of PABPC1 is finely modulated by diverse PTMs, including methylation, small ubiquitin‐like modification (SUMOylation), acetylation, and ubiquitination, with modification sites distributed across its structural domains [9, 35]. For instance, coactivator associated arginine methyltransferase 1 (CARM1) mediated asymmetric dimethylation of arginine 493 (R493me2a) is involved in regulating PABPC1 function [36]. Notably, under oxidative stress, hypoxia, or chemotherapeutic drug exposure, PABPC1 undergoes SUMOylation [37]. This modification promotes its recruitment to stress granules (SGs) and selectively stabilizes U rich element containing mRNAs, thereby enhancing the survival capacity of tumor cells under adverse microenvironmental conditions. Moreover, emerging evidence indicates that PABPC1 can be acetylated at K167 by arrest defective 1 (ARD1), which increases its cytoplasmic retention and cooperates with eIF4G to stabilize glutamate‐cysteine ligase catalytic subunit (GCLC) mRNA, thus promoting glutathione synthesis and ferroptosis resistance in hepatocellular carcinoma (HCC) [38]. In addition, PABPC1 has recently been identified as a deubiquitination substrate of ubiquitin specific peptidase 39 (USP39); its neddylation by ubiquitin conjugating enzyme E2M (UBE2M) stabilizes PABPC1 and enhances cyclin B1 translation, driving cell cycle progression in colorectal cancer [39]. The interplay between different PTMs on PABPC1, for example SUMOylation versus acetylation, may create a “PTM code” that dictates its subcellular localization and partner selection [40]. Collectively, these observations position PABPC1 as a key regulatory node that integrates post transcriptional regulation and PTM signaling.

These representative PTMs of PABPC1 are summarized in Table 1.

TABLE 1.

Representative post‐translational modifications of PABPC1.

Modification	Enzyme	Stimuli	Functional impact on PABPC1	Outcome	References
Ubiquitination	SPOP, MKRN	Normal	Tagging PABPC1 via non‐degradative ubiquitination, consequently modulating global protein synthesis	Inhibit cell proliferation	[35]
Methylation	CARM1	Normal	Modulating the interaction of PABPC1 with core translation factors	Maintain translational regulation	[36]
SUMOylation	E3 enzyme	Oxidative stress, hypoxia, chemotherapy	Promoting the dissociation of PABPC1 from translationally active polyribosomes and its physical recruitment into the scaffold of stress granules	Promoting tumor survival	[37]
Acetylation	ARD1	Normal and metabolic stress	Abrogating the nuclear import of PABPC1, thereby increasing its cytoplasmic effective concentration, while concurrently exposing the eIF4G‐binding epitope to facilitate physical interaction	Promoting ferroptosis resistance in cells	[38]
Deubiquitination	USP39	Normal	Ubiquitin‐conjugating enzyme E2 M promoting the neddylation of USP39, which in turn enhancing the deubiquitinating activity of USP39 toward PABPC1, thereby stabilizing the PABPC1 protein	Driving G2/M phase transition in cells	[39]

Abbreviation: SPOP, speckle‐type POZ protein.

3. New Insights Into PABPC1 Function: From Linear Regulation to Multidimensional Networks

3.1. Phase Separation and Selective Translation

Liquid–liquid phase separation (LLPS) driven formation of biomolecular condensates is an important mechanism that enables cells to cope with stress and achieve spatiotemporally controlled gene regulation [41, 42, 43, 44]. Recently, PABPC1 has emerged as a key player in this process under stress conditions [45]. Using CRISPR‐Cas9 screening, Sun et al. [46] identified PABPC1 as a critical driver of blast crisis in chronic myeloid leukemia (CML) and, for the first time, demonstrated that PABPC1 forms biomolecular condensates via LLPS to mediate selective translational enhancement of specific mRNAs. Mechanistically, this selectivity depends on PABPC1's phase‐separation capacity rather than differential RNA‐binding affinity. Within condensates, enriched translation initiation factors and specific mRNAs with long structured 5′UTRs form functional “translation factories” [47, 48]. This compartmentalization enables PABPC1 to preferentially boost leukemogenic mRNA translation over housekeeping transcripts, directly linking LLPS to therapy resistance: by selectively upregulating pro‐survival and antioxidant mRNAs, condensates enhance tumor cell fitness against oxidative stress, nutrient deprivation, and chemotherapeutic insults. Notably, upstream PTMs (detailed in Section 2.1) tightly regulate this phase‐separation behavior: SUMOylation promotes SG recruitment, while K167 acetylation modulates condensation dynamics and cytoplasmic retention [37, 38]. These modifications act as rheostats that fine‐tune condensate material properties and substrate selectivity, bridging LLPS with upstream signaling pathways. Collectively, these findings expand PABPC1's role from a global housekeeper to a selective amplifier and offer new therapeutic entry points [49, 50].

3.2. The Non‐Coding RNA‐PABPC1 Axis

Emerging evidence has established that both lncRNAs and circRNAs can directly bind to PABPC1, thereby modulating its stability, subcellular localization, or mRNA target selectivity under basal and stress conditions. These interactions constitute critical regulatory axes in tumor progression and other diseases.

LncRNA mediated regulation of PABPC1 occurs through multiple mechanisms. In breast cancer, LINC00882 directly binds PABPC1 and enhances its association with ETS domain‐containing protein Elk‐3 (ELK3) mRNA, leading to ELK3 stabilization and increased protein expression [20]. Notably, the cellular abundance of LINC00882 is tightly governed by upstream layers of regulation: it is transcriptionally activated by CCAAT/enhancer‐binding protein beta (C/EBPβ) and post‐transcriptionally stabilized by methyltransferase‐like 14 (METTL14)‐dependent m⁶A modification recognized by insulin‐like growth factor 2 mRNA‐binding protein 2 (IGF2BP2). Through this regulatory cascade, PABPC1 acts as a downstream effector that translates altered LINC00882 levels into changes in ELK3 mRNA stability, thereby exemplifying how upstream transcriptional and epitranscriptional signals converge on the noncoding RNA‐PABPC1 axis to modulate gene expression. Similarly, lncRNA PRBC physically interacts with PABPC1 and promotes its nuclear to cytoplasmic translocation, driving breast cancer progression [51]. By contrast, in non‐small cell lung cancer (NSCLC), LINC00467 facilitates the interaction between PABPC1 and the E3 ubiquitin ligase E4B (UBE4B), enhancing proteasome‐dependent PABPC1 degradation [52]. The resulting downregulation of PABPC1 affects wingless‐type MMTV integration site family (Wnt)/β‐catenin activity and promotes tumor progression, indicating that PABPC1's oncogenic role may not be strictly dependent on high expression levels. Beyond these, lncRNAs can epigenetically regulate PABPC1 expression: SNHG14 increases H3K27 acetylation in the PABPC1 promoter, upregulating PABPC1 [53]. Additional examples include WDR11 AS1 (stabilizing SRY‐box transcription factor 9 (SOX9) mRNA in osteoarthritis), exosomal TRPM2 AS (enhancing PABPC1 mediated NUMB endocytic adaptor protein (NUMB) suppression and notch receptor 1 (NOTCH1) activation in gallbladder cancer), conserved metabolic regulators (binding PABPC1 via short motifs to control the amino acid‐mTOR‐sterol regulatory element‐binding protein 1 (SREBP1) axis), and lncRNA ATB as a PABPC1 interacting partner [54, 55, 56, 57].

CircRNA‐PABPC1 interactions add another layer of complexity. Under glucose deprivation induced energy stress, c‐Myc upregulated circDDX21, which directly binds PABPC1, disrupting the PABPC1‐makorin RING‐finger protein 3 (MKRN3) interaction and attenuating MKRN3 mediated ubiquitin dependent degradation of PABPC1 [58]. This stabilizes PABPC1, which in turn binds and stabilizes phosphoglycerate mutase 1 (PGAM1) mRNA, promoting glycolysis. In bladder cancer, circPTK2 promotes epithelial‐mesenchymal transition (EMT) driven metastasis and gemcitabine resistance via the PABPC1/SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) axis [59], while circSTX6 enhances suppressor of zeste 12 homolog (SUZ12) mRNA stability by binding PABPC1, facilitating metastasis and cisplatin resistance [60]. CircFOXK2 interacts with PABPC1 and correlates with NSCLC progression and metastasis [61]. Lastly, circ_PABPC1, highly expressed in gastric cancer, directly binds integrin linked kinase (ILK) to prevent its degradation, thereby activating the nuclear factor kappa B (NF‐κB) pathway and promoting proliferation, migration, and invasion [62].

Thus, lncRNAs and circRNAs regulate PABPC1 through diverse mechanisms, affecting its stability, subcellular distribution, and mRNA target choice in a cancer‐ and disease‐specific manner.

The PABPC1‐associated lncRNAs and circRNAs are summarized in Table 2.

TABLE 2.

Summary of PABPC1‐associated lncRNAs and circRNAs.

Type	Name	Positive/negative	Regulatory mechanism	Related disease/process	References
LncRNA	LINC00882	Positive	Directly bind to PABPC1 and promote the interaction between PABPC1 and ELK3 mRNA, thereby stabilizing ELK3 mRNA	Breast cancer	[20]
LncRNA	LncRNA PRBC	Positive	Physically binding PABPC1 and promoting its transport from the nucleus to the cytoplasm	Breast cancer	[51]
LncRNA	LncRNA SNHG14	Positive	Upregulation of PABPC1 expression at the transcriptional level through histone H3K27 acetylation modification	Breast cancer	[53]
LncRNA	LncRNA WDR11‐AS1	Positive	Directly binding to PABPC1 in osteoarthritis, synergistically stabilizing SOX9 mRNA	Osteoarthritis	[54]
LncRNA	LncRNA TRPM2‐AS	Positive	Enhance the inhibition of NUMB mRNA expression mediated by PABPC1, activate the NOTCH1 signaling pathway, and promote angiogenesis.	Gallbladder cancer	[55]
LncRNA	LncRNA‐ATB	Positive	Confirmed as target protein of PABPC1 through RNA pull‐down and RIP experiments	Severe eclampsia	[57]
LncRNA	LINC00467	Negative	Promote the binding of PABPC1 to UBE4B, leading to the degradation of PABPC1 through the ubiquitin proteasome pathway	Non small cell lung cancer	[52]
LncRNA	LncRNA LMR1	Negative	Binding with PABPC1, inhibiting protein translation, regulating the amino acid‐mTOR‐SREBP1 metabolic axis	Metabolic regulation	[56]
CircRNA	CircDDX21	Positive	Combining with PABPC1, reducing its ubiquitination enhances its binding and stability with PGAM1 mRNA, promoting glycolysis and carcinogenesis	Hepatocellular carcinoma	[58]
CircRNA	CircPTK2	Positive	Bind to PABPC1 and enhance its ability to stabilize SETDB1 mRNA	Bladder cancer	[59]
CircRNA	CircFOXK2	Positive	Forming a complex with PABPC1 increases the stability of STMN1 mRNA, promotes its transcription and translation, and drives cancer progression and metastasis	Non small cell lung cancer	[61]
CircRNA	CircSTX6	Negative	Reduce the level of PABPC1 and combine with it to increase the stability of downstream target, and promote the metastasis of bladder cancer and chemotherapy resistance	Bladder cancer	[60]

Abbreviations: RIP, RNA immunoprecipitation experiment; STMN1, stathmin 1.

3.3. Alternative Polyadenylation Regulation by PABPC1

APA generates mRNA isoforms with distinct 3′UTR lengths by selecting different poly(A) sites [63], thereby affecting mRNA stability, translation efficiency, and subcellular localization [63, 64, 65, 66]. Longer 3′UTRs typically harbor more binding sites for miRNAs and RBPs [67], whereas shorter 3′UTRs tend to evade miRNA‐mediated repression, enhancing protein output [68]. PABPC1, which shuttles between the nucleus and cytoplasm, directly participates in APA regulation through interactions with core 3′ end processing factors.

A systematic siRNA knockdown coupled with deep sequencing revealed that among core 3′ processing factors, PCF11 cleavage and polyadenylation factor subunit (PCF11) and FIP1 like 1 (FIP1L1) predominantly promote proximal poly(A) site usage, whereas CFI 25/68, poly(A)‐binding protein nuclear 1 (PABPN1), and PABPC1 favor distal poly(A) site usage. Accordingly, PABPC1 knockdown globally shortens 3′UTRs, indicating that PABPC1 promotes full length 3′UTR isoforms [69].

A direct link between PABPC1 and APA in cancer was established in liver cancer stem cells. The solute carrier family 27 member 5 (SLC27A5)‐PABPC1‐METTL14 axis regulates stemness maintenance: SLC27A5 promotes retinoblastoma‐binding protein 7 (RBBP7) dependent ubiquitination and degradation of PABPC1, reducing PABPC1 protein levels and shifting the 3′UTR usage of METTL14 toward its short isoform (METTL14_US). METTL14 functions as a tumor suppressor that restricts stemness, and the METTL14_US isoform enhances METTL14 protein expression by removing inhibitory elements present in the long 3′UTR, thereby increasing translational efficiency and/or mRNA stability. Consequently, increased METTL14 protein suppresses stemness. Conversely, SLC27A5 loss leads to PABPC1 accumulation and decreased METTL14 expression, driving tumor progression. These findings directly implicate PABPC1 in APA regulation. Therapeutically targeting PABPC1 or its downstream oncogenic APA events, particularly in SLC27A5‐deficient tumors, may represent a more rational and effective strategy to restore the tumor‐suppressive APA pattern and inhibit stemness [70].

In erythroid progenitors, elevated PABPC1 levels increase proximal poly(A) site usage in the TSC22 Domain Family Member 1 (TSC22D1) gene, enhancing TSC22D1 expression and revealing an APA dependent mechanism that controls erythroid expansion and differentiation [71]. Furthermore, PABPC1 collaborates with other RBPs to achieve cell type specific APA regulation. In plasma cells, PABPC1 binds hnRNP L‐Like protein (hnRNPLL) and recruits it to the 3′ end of immunoglobulin heavy chain mRNA, facilitating the switch from membrane bound to secreted isoform. This process depends on APA and on PABPC1's ability to bind the poly(A) tail, providing a stable platform for hnRNPLL to precisely control immunoglobulin secretion [72].

PABPC1 functions in APA processes are summarized in Table 3.

TABLE 3.

Summary of PABPC1 functions in alternative polyadenylation processes.

Related genes/pathways	Regulatory mechanism	Physiological/pathological process	References
Genome wide 3′UTR‐APA	PABPC1 collaborates with CFI‐25/68 and PABPN1 to systematically promote the use of distal poly (A) sites	PABPC1 globally promotes the use of distal poly (A) sites	[69]
METTL14/SLC27A5‐PABPC1‐METTL14	SLC27A5 downregulates PABPC1 protein levels through RBBP7 mediated ubiquitination degradation of PABPC1; the reduction of PABPC1 promotes the use of proximal poly (A) sites, resulting in a shortened 3′UTR of METTL14	Inhibiting tumor stemness in Hepatocellular carcinoma	[70]

TSC22D1	PABPC1 is the main regulatory factor for the dynamic regulation of alternative polyadenylation in the early stage of erythroid differentiation; knocking down PABPC1 promotes the use of the proximal poly (A) site, resulting in a shortened 3′UTR	Regulating the proliferation and differentiation of erythroid progenitor cells	[71]
IgH gene	PABPC1 serves as a molecular scaffold that binds to the poly(A) tail of mRNA and recruits hnRNPLL to the 3′ end of IgH mRNA, thereby providing a platform for the precise selection of APA sites.	Facilitating the switch of IgH from membrane‐bound to secreted isoform	[72]

Abbreviation: IgH, immunoglobulin heavy chain.

3.4. Additional Regulatory Mechanisms

Beyond its roles in phase separation, noncoding RNA networks, and APA, PABPC1 participates in several other regulatory mechanisms. Under various stress conditions, PABPC1 is recruited to SGs [73, 74, 75]; it promotes SG assembly through its MLLE domain by interacting with PAM2‐containing proteins such as ataxin 2. Multiple viruses selectively inhibit host translation by cleaving PABPC1, competing for eIF4G binding, or inducing its nuclear retention [76, 77, 78, 79]. PABPC1 can shuttle between the nucleus and the cytoplasm and participates in pre‐mRNA splicing as a component of the spliceosomal C complex. In the DNA damage response, mitogen‐activated protein kinase‐activated protein kinase 2 (MK2)‐mediated phosphorylation of PABPC1 at Ser470 promotes its interaction with 14‐3‐3 proteins, thereby regulating cell fate decisions [80]. Human pumilio homolog 1 and 2 (PUM1/2) proteins achieve post‐transcriptional repression by accelerating the degradation of target mRNAs, and they directly bind to PABPC1 and depend on it to exert their repressive function [25].

3.5. Functional Duality: Pro‐ Versus Anti‐ Tumor Effects of PABPC1

Accumulating evidence indicates that PABPC1 plays a dual role in tumor biology, exhibiting predominantly pro‐tumorigenic activities in most cancer types while also displaying context‐dependent tumor suppressive functions.

Pro‐tumor effects have been reported in multiple malignancies. PABPC1 is commonly overexpressed in multiple malignancies, including lung, gastric, pancreatic, hepatocellular, papillary renal cell, breast, and nasopharyngeal carcinomas, and its high expression is consistently associated with poor prognosis [11, 12, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91]. Mechanistically, PABPC1 promotes tumor progression by serving as a scaffolding protein that interacts with phospholipase C beta 1 (PLCB1) and phosphoinositide 3‐kinase (PI3K) to amplify PLCB1‐mediated PI3K/AKT serine/threonine kinase (AKT) signaling, which in turn facilitates EMT and mediates phase separation‐dependent selective translation [46, 92, 93]. Post‐translational modifications, including MKRN3‐mediated ubiquitination and stress‐induced SUMOylation, further enhance its oncogenic functions [37, 58, 94].

Conversely, tumor suppressive roles of PABPC1 have also been uncovered. In glioma, PABPC1 interacts with and stabilizes the lncRNA BDNF‐AS, which subsequently promotes retina and anterior neural fold homeobox 2 (RAX2) mRNA degradation, leading to discs large homolog 5 (DLG5) upregulation and activation of the Hippo pathway, thereby inhibiting malignant behaviors [95, 96]. In cervical cancer, PABPC1 is recruited by the tumor suppressor PDHB AS to suppress the expression of the oncogene Wnt7b [97]. Additionally, the role of PABPC1 in thyroid cancer is unclear [98].

The expression patterns and functional outcomes of PABPC1 across different tumor types are summarized in Table 4.

TABLE 4.

The role and prognostic impact of PABPC1 in cancers.

Type	Expression	Pro‐tumor/Anti‐tumor	Impact on patient prognosis/function	References
Nasopharyngeal carcinoma	High	Pro‐tumor	Poor prognosis, OS and DFS of patients with high expression were worse	[8]
Ovarian cancer	High	Pro‐tumor	Poor prognosis, high expression was associated with shortened patient survival; silencing PABPC1 inhibited the proliferation, invasion, and migration of ovarian cancer cells	[11]
Chronic myeloid leukemia	High	Pro‐tumor	Promoting disease progression, PABPC1 prioritized improving the translation efficiency of pathogenic mRNAs with long 5′ UTR structures, inhibition of PABPC1 suppressed cell proliferation and disease progression	[46]
Bladder cancer	High	Pro‐tumor	Poor prognosis, PABPC1 positivity was a risk factor that affected prognosis and is positively correlated with EMT indicators	[59]
Gastric cancer	High	Pro‐tumor	Poor prognosis, high expression was associated with tumor size, Borrmann classification, vascular invasion, depth of invasion, and lymph node metastasis	[81], [92]
Renal cancer	High	Pro‐tumor	Poor prognosis, high expression was significantly associated with poorer survival, and was associated with sunitinib resistance	[82], [99]
Pancreatic cancer	High	Pro‐tumor	Poor prognosis, PABPC1 was up‐regulated in pancreatic cancer, and high expression was associated with poor prognosis of patients, functionally promoted cell proliferation and metastasis	[83], [103]
Hepatocellular carcinoma	High	Pro‐tumor	Poor prognosis, high expression was an independent prognostic risk factor for OS, and was associated with TNM staging and serum AFP levels	[85]
Colorectal cancer	High	Pro‐tumor	Poor prognosis, PABPC1L expression was significantly correlated with age, pathological stage, lymph node metastasis, distant metastasis, and patient death	[86], [87]
Esophageal squamous cell carcinoma	High	Pro‐tumor	Poor prognosis, high expression was significantly associated with lymph node metastasis, pathological staging, and tumor recurrence, and was an independent prognostic factor for OS	[88]
Lung cancer	High	Pro‐tumor	Poor prognosis, PABPC1 was a potential prognostic marker, and functional validation showed that it promotes lung cancer cell proliferation	[89], [91]
Breast cancer	High	Pro‐tumor	Poor prognosis, in addition to Luminal A type, high expression was an independent poor prognostic factor of OS and DFS, which was helpful for classification of breast cancer and selection of postoperative scheme	[90]
Glioma	Low	Anti‐tumor	Good prognosis, PABPC1 expression was downregulated in high‐grade gliomas, and patients with high expression of PABPC1 had a longer survival time, making it a positive prognostic factor	[95], [96]
Cervical cancer	Unclear	Putative anti‐tumor	Tumor suppressor PDHB‐AS recruited PABPC1 and suppressed the expression of the pro‐tumor gene Wnt7b	[97]
Thyroid cancer	Unclear	Unclear	PABPC1 gene mutation detected in follicular thyroid carcinoma suggested its possible involvement in the occurrence and development of follicular thyroid carcinoma, but its clinical prognostic association required further research	[98]

Abbreviations: AFP, alpha‐fetoprotein; DFS, disease‐free survival; OS overall survival; PDHB‐AS, PDHB antisense RNA; TNM, tumor‐node‐metastasis.

4. Cross Talk With Classical Tumor Signaling Pathways

Although PABPC1 does not directly interact with classical tumor suppressor proteins such as p53, it broadly influences multiple tumor‐related pathways through post‐transcriptional regulation. Emerging evidence reveals two predominant mechanistic patterns: PABPC1 acts as an upstream post‐transcriptional regulator that controls the stability or translation of key signaling mRNAs, and it simultaneously serves as a downstream effector whose expression is modulated by oncogenic signals or epigenetic modifications.

As an upstream regulator, PABPC1 directly binds to and modulates the fate of mRNAs encoding critical pathway components. For example, it interacts with eIF4G to enhance interferon alpha‐inducible protein 27 (IFI27) mRNA stability, activating the interferon pathway, and stabilizes p21‐activated kinase 1 (PAK1) mRNA to promote gastric cancer metastasis [100, 101]. Through interaction with argonaute 2 and miR‐31‐5p, PABPC1 suppresses NUMB mRNA, thereby de‐repressing NOTCH1 signaling [55]. PABPC1 is associated with PI3K/AKT pathway [92, 102]. In the PI3K/AKT cascade, PABPC1 cooperates with PLCB1 or maintains the expression of upstream activators to sustain oncogenic output [104]. Moreover, its interplay with La‐related protein 1 (LARP1) competitively regulates the translation or degradation of Wnt/β‐catenin pathway mRNAs [103].

Conversely, PABPC1 itself is a downstream target of several regulatory circuits. LncRNAs such as SNHG14 upregulate PABPC1 via H3K27 acetylation at its promoter, thereby fueling phosphatase and tensin homolog (PTEN) and nuclear factor erythroid 2‐related factor 2 (NRF2) signaling [9, 53, 104]. The lncRNA ATB positively modulates PABPC1 expression through the p53/MDM2 axis [57]. In addition, circ‐PABPC1 protects the ILK protein from degradation, leading to NF‐κB pathway activation and creating a feed‐forward oncogenic loop [62].

Collectively, PABPC1 functions as a bidirectional translational node that integrates diverse upstream signals to modulate multiple signaling outputs post‐transcriptionally (Table 5).

TABLE 5.

Summary of signaling pathways associated with PABPC1.

Signaling pathway	Regulatory mechanism	Tumor type	References
Wnt/β‐catenin pathway	In non small cell lung cancer, LINC00467 modulated this pathway via PABPC1 degradation, whereas in hepatoblastoma LARP1 competitively binded PABPC1 and promoted DKK4 mRNA degradation to negatively regulate Wnt/β‐catenin signaling	Non small cell lung cancer, Hepatoblastoma	[52], [104]
Nrf2 pathway	LncRNA SNHG14 upregulated PABPC1 expression via H3K27 acetylation, thereby activating this pathway and contributing to trastuzumab resistance in breast cancer	Breast cancer	[53]
NOTCH1 pathway	PABPC1 interacted with argonaute 2 and miR‐31‐5p to suppress NUMB mRNA expression, thereby activating the NOTCH1 pathway and promoting angiogenesis in gallbladder cancer	Gallbladder cancer	[55]
p53 pathway	GSEA analysis revealed that PABPC1 expression is closely associated with the p53 signaling pathway in hepatocellular carcinoma; lncRNA ATB regulated PABPC1 expression through the p53/MDM2 pathway	Hepatocellular carcinoma	[57], [85]
PI3K/AKT pathway	Knockdown of PABPC1 reduced the expression of p‐PI3K and p‐AKT, thereby suppressing cancer cell proliferation, migration, and EMT; PABPC1 overexpression activated this pathway in multiple cancer types	Gastric cancer, pancreatic cancer, bile duct cancer	[92], [102, 103]
PTEN pathway	LncRNA SNHG14 upregulated PABPC1 through H3K27 acetylation, and subsequently promoted tumor progression via the PTEN pathway	Hepatocellular carcinoma	[105]
IFN/IFI27 pathway	PABPC1 interacted with eIF4G to enhance IFI27 mRNA stability, thereby activating this pathway and promoting proliferation and invasion of esophageal squamous cell carcinoma	Esophageal squamous cell carcinoma	[100]
PAK1 pathway	PABPC1 promoted gastric cancer metastasis by enhancing PAK1 mRNA stability, which facilitated the EMT process	Gastric cancer	[101]

Abbreviations: DKK4, dickkopf‐related protein 4; GSEA, gene set enrichment analysis; IFN/IFI27, interferon/interferon alpha‐inducible protein 27.

5. PABPC1 In Therapy Resistance: From TKI Resistance to Stress Resistance

The role of PABPC1 in tumor therapy resistance has attracted considerable attention. The spectrum of resistance in which PABPC1 is implicated has expanded from tyrosine kinase inhibitor (TKI) resistance to stress resistance and even immunotherapy resistance [106], highlighting its importance as a common hub for therapy resistance.

In CML, PABPC1 forms biomolecular condensates via LLPS at high concentrations, preferentially enhancing the translation of BCR‐ABL1 transcripts, including those carrying TKI‐resistance mutations, both of which harbor long and highly structured 5′UTRs, thereby representing a major mechanism of acquired resistance [46]. PABPC1 is significantly upregulated in TKI‐resistant CML cells, and its inhibition overcomes TKI resistance.

In bladder cancer, Meng et al. [59] revealed that the circPTK2/PABPC1/SETDB1 axis promotes EMT‐mediated tumor metastasis and gemcitabine resistance. In HCC, a study uncovered a novel mechanism of ferroptosis resistance: ARD1 acetylates PABPC1 at lysine 167, disrupting the formation of the PABPC1‐importin α7 complex and enhancing its cytoplasmic retention. Cytoplasmic PABPC1 then cooperates with eIF4G to stabilize GCLC mRNA, increasing glutathione synthesis and thereby conferring resistance to sorafenib‐induced ferroptosis [38].

In triple negative breast cancer (TNBC), the natural Ganoderma meroterpenoid LZ22 effectively suppresses cancer cell proliferation, and PABPC1 was identified as the key target mediating the anti‐TNBC activity of LZ22 [107]. In nasopharyngeal carcinoma, high PABPC1 expression is significantly associated with poor overall survival, independent of chemoradiotherapy regimens. While this association could reflect intrinsic aggressive tumor biology, it also raises the possibility of a contributory role in chemoresistance, a hypothesis that warrants further investigation using direct treatment‐response endpoints, such as progression‐free survival or objective response rate [11]. Under stress conditions, PABPC1 undergoes SUMOylation, which stabilizes U‐rich element containing mitophagy‐related mRNAs and enhances the tolerance of cancer cells to chemotherapy‐induced oxidative stress [37].

A recent study demonstrated that PABPC1 is markedly upregulated in clear cell renal cell carcinoma (ccRCC) and promotes tumor cell proliferation, migration, invasion, and sunitinib resistance by stabilizing phosphoglycerate kinase 1 (PGK1) mRNA through direct binding [99]. Furthermore, the paralog PABPC1‐like protein (PABPC1L) plays an important role in immunotherapy resistance. It is worth noting that PABPC1L is a distinct paralog with partially divergent functions; its roles should not be directly extrapolated from those of PABPC1. In renal cell carcinoma, PABPC1L enhances the stability of janus kinase 2 (JAK2) mRNA, activates the JAK2‐signal transducer and activator of transcription 1 (STAT1) signaling pathway, upregulates indoleamine 2,3‐dioxygenase 1 (IDO1) expression, promotes tryptophan metabolism, and induces T cell dysfunction and Treg infiltration, thereby fostering an immunosuppressive microenvironment [108]. This functional divergence between PABPC1 and PABPC1L suggests paralog specific roles in therapy resistance, which could be exploited for selective targeting.

Collectively, these findings indicate that PABPC1 lies at the intersection of multiple therapy resistance mechanisms. Targeting PABPC1 and its associated regulatory networks holds promise for developing novel combination strategies to reverse tumor therapy resistance [109]. The role of PABPC1 in therapy resistance is summarized in Figure 2.

FIGURE 2.

Summary of PABPC1 as a key factor in tumor drug tolerance and stress resistance.

6. Conclusion and Future Perspectives

The core value of PABPC1 in cancer can be defined as a stress responsive translation reprogramming hub. Its functions constitute an integrated regulatory network spanning four levels: molecular, cellular, tumor evolution, and clinical translation (Figure 3).

FIGURE 3.

PABPC1 is a tress responsive translation reprogramming hub in cancer.

At the molecular level, PABPC1 forms biomolecular condensates through LLPS, selectively enhancing the translation of oncogenic mRNAs with long and highly structured 5′UTRs. This enables tumor cells to rapidly remodel their proteome without altering the transcriptome, acting as a “translational switch.” Moreover, PABPC1 responds to stress signals via PTMs such as SUMOylation, recruiting protective mRNAs to SGs and synergistically maintaining cell survival. Through non‐coding RNA interaction networks, it regulates its own stability and target selectivity, and through APA it influences 3′UTR length.

At the cellular level, PABPC1 resides at the convergence point of multiple signaling pathways, including PI3K/AKT, Wnt/β‐catenin, NF‐κB, NOTCH, and p53, converting upstream signals into translational outputs. Its functional duality is closely linked to tumor type and microenvironment, reflecting its context‐dependent nature.

At the tumor evolution level, PABPC1 endows tumor cells with translational plasticity, enabling adaptation to stress conditions such as nutrient deprivation, hypoxia, chemotherapy, and immune attack, thereby driving early onset, metastasis, and therapy resistance [110]. It drives TKI resistance through phase separation mediated selective translation, mediates chemotherapy resistance and ferroptosis evasion through acetylation/deubiquitination modifications, and its paralog PABPC1L promotes immunotherapy resistance via the JAK2‐STAT1‐IDO1 axis.

At the clinical translation level, the dependence of tumor cells on PABPC1 is much higher than that of normal cells, highlighting a selective dependency that may provide a therapeutic window for targeted intervention [46, 83]. High PABPC1 expression is an independent poor prognostic factor in breast cancer, pancreatic cancer, and other malignancies, and may guide treatment selection. Combining PABPC1 inhibitors with existing therapies holds promise for dual blockade of transcription and translation, reversing drug resistance and improving therapeutic efficacy.

Beyond PABPC1, it is important to recognize that other members of the PABP family are also increasingly implicated in cancer biology [9]. PABPC4 is frequently overexpressed in cancers, where it promotes proliferation, migration, and stemness, correlating with adverse clinical outcomes [111]. PABPN1, the major nuclear PABP, participates in APA dysregulation across multiple tumor types and has been proposed as a pan‐cancer prognostic and immune‐related biomarker [112, 113, 114, 115]. PABPC5 has also been reported to exert oncogenic functions in glioma [116, 117]. These observations collectively indicate that PABPC1 is not the sole oncogenic PABP family member. However, whether these family members function antagonistically or cooperatively with PABPC1 in a context‐dependent manner, and how their relative expression or modification states influence tumor progression and therapy response, remains largely unexplored and warrants dedicated investigation.

Moreover, the pathophysiological impact of PABPC1 is not confined to malignancy. Dysregulation of PABPC1 has been increasingly documented in diverse non‐malignant conditions: pathogenic variants impair neurogenesis and associate with developmental delay [118], while cardiac re‐expression drives pathological hypertrophy and occurs after myocardial injury [34]; inflammatory contexts implicate PABPC1 in suppressing macrophage cytokine release and as an autoantigen in lupus [119]; multiple viruses hijack it to subvert host translation [79]. These observations underscore that PABPC1's relevance extends far beyond cancer, providing a broader framework for its context‐dependent functions and raising additional questions that merit attention alongside the tumor‐specific issues.

Several key questions remain. First, what triggers PABPC1 phase separation in vivo, and how do PTMs modulate condensate properties? Second, the functional duality of PABPC1 requires systematic dissection using single cell and spatial approaches. Third, therapeutic targeting of PABPC1 is promising. Known inhibitors such as 1,10‐Phenanthroline, ML324, and LZ22 (and its derivative LZ22‐4) [46, 107], all disrupt PABPC1‐RNA binding or translation. Future work should optimize these into selective, bioavailable candidates for preclinical testing. Fourth, the potential involvement of PABPC1 in RNA modification crosstalk remains virtually unexplored and could reveal new layers of regulation.

In summary, while PABPC1 is markedly overexpressed in cancer, the upstream drivers remain incompletely understood. Current evidence points to a convergence of transcriptional activation, lncRNA/circRNA networks, and ubiquitin‐deubiquitin balance that modulate PABPC1 expression and stability. However, it remains unclear how these layers are coordinated, whether oncogenic signals drive upregulation, and if gene amplification is broadly relevant beyond cancer. Nevertheless, PABPC1 clearly bridges stress sensing, translation reprogramming, and therapy resistance. Its transition from a linear housekeeper to a dynamic phase‐separation coordinator reshapes our view of post‐transcriptional regulation in cancer. Future efforts should unravel the physical chemistry of its condensates and regulatory networks while systematically addressing the upstream regulatory landscape: such integrative approaches will deepen our understanding of cancer biology and open new avenues for precision medicine.

Author Contributions

Cuiwei Zhang: writing – original draft, visualization, validation, investigation. Ye Zhu: writing – review and editing, validation, investigation. Wenbo Long: conceptualization, writing – review and editing, visualization, validation, supervision, methodology.

Funding

This study was supported by grants from the Science and Technology Strategic Cooperation Programs of Luzhou Municipal People's Government and Southwest Medical University (No. 2024LZXNYDJ036 and No. 2024LZXNYDJ077), the scientific research project of Southwest Medical University (No. 2025JC036).

Disclosure

The authors have nothing to report.

Ethics Statement

The authors have nothing to report.

Consent

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.