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Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review)

  • Authors:
    • Rui Zhang
    • Yiwen Lu
    • Xiaohua Fang
    • Fengquan Zhang
    • Weidong Wu
    • Jie Song
    • Zhenzhen Liang
  • View Affiliations / Copyright

    Affiliations: School of Public Health, Henan Medical University, Xinxiang, Henan 453003, P.R. China, Health Service Center, Zhuhai Road Street Community, Shinan, Qingdao, Shandong 266071, P.R. China, School of Public Health, Henan Medical University, Xinxiang, Henan 453003, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 258
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    Published online on: April 23, 2026
       https://doi.org/10.3892/ol.2026.15613
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Abstract

Gastrointestinal (GI) cancer remains a leading cause of cancer‑related mortality worldwide, with epigenetic alterations progressively recognized as key drivers of tumorigenesis and therapeutic resistance. Through its role in facilitating cell proliferation, inhibiting apoptosis, driving epithelial‑mesenchymal transition (EMT) and metastasis, reinforcing angiogenesis, inducing metabolic reprogramming, mediating chemoradiotherapy resistance and maintaining cancer stem cell (CSC) properties, protein arginine methyltransferase 5 (PRMT5) has emerged as a key oncogenic regulator among these epigenetic modifiers implicated in GI cancer progression. Elevated PRMT5 expression has been observed in multiple GI cancer subtypes, comprising gastric cancer (GC), colorectal cancer (CRC), hepatocellular carcinoma (HCC) and pancreatic cancer, where PRMT5 markedly contributes to tumorigenesis via symmetric dimethylation of histone (e.g., dimethylation of histone H4 at arginine 3) and non‑histone substrates [e.g., AKT1 and sterol regulatory element‑binding protein 1a (SREBP1a)]. In GC, PRMT5 activates the PI3K/AKT pathway [e.g., by methylating AKT1 at arginine (R)391 and upregulating c‑Myc], facilitating tumor cell proliferation and survival. In CRC, PRMT5‑mediated methylation of SMAD4 (e.g., at R361) reinforces TGF‑β signaling, facilitating EMT and metastasis, while its interaction with EGFR further amplifies proliferative signals. PRMT5 also upregulates VEGF expression (e.g., via chromatin remodeling at its promoter), stimulating angiogenesis and inhibits ferroptosis (e.g., by suppressing the solute carrier family 7 member 11/glutathione peroxidase 4 axis in HCC), supporting tumor survival. Furthermore, PRMT5 markedly contributes to metabolic reprogramming (e.g., accelerating de novo lipogenesis via SREBP1a methylation and glycolysis via epigenetic silencing of F‑box and WD repeat domain‑containing protein 7), while strengthening DNA repair (e.g., homologous recombination) and CSC self‑renewal (e.g., via the β‑catenin/IL‑8 axis in CRC) to confer therapy resistance. However, PRMT5 inhibitors (e.g., GSK3326595 and JNJ‑64619178) demonstrate antitumor effects in preclinical models and methylthioadenosine phosphorylase (MTAP) deletion may serve as a potential biomarker for patient selection. The clinical translation of PRMT5 inhibitors is limited by hematological toxicity, lack of robust predictive biomarkers beyond MTAP and potential resistance from compensatory PRMT family members. It is key to clarify GI cancer‑specific PRMT5 mechanisms and potentially develop optimized combination therapies in the future.
View Figures

Figure 1

Biological function of PRMT5 in
gastrointestinal cancer. PRMT5 regulates the expression levels of
AKT, p53 and more through histone methylation modification, and
participates in the biological processes of gastrointestinal
cancer, encompassing cell-cycle expansion, programmed cell death,
neovascularization, motility, tissue penetration and
radioresistance. PRMT5, protein arginine methyltransferase 5; EMT,
epithelial-mesenchymal transition; HDGF, hepatoma-derived growth
factor; HGF, hepatoma growth factor; CDKN2B, CDK inhibitor 2B;
AURKB, aurora kinase B; EZH2, enhancer of zeste homolog 2; FOXP1,
forkhead box protein P1.

Figure 2

Downstream region of PRMT5. Apoptosis
regulatory pathway: core genes comprise Bcl-2, Bax and Caspase 3,
which collectively participate in the regulation of the initiation
and execution of apoptosis. Transcriptional regulation pathway:
Comprising pivotal molecules such as p53, STAT3, NF-κB, ATM, BRCA1
and NLRP3, these genes are involved in signal transduction and
expression regulation of multifarious cellular functions through
transcriptional regulation. Cell cycle control pathway: The
paramount components are pRb, CDK4 and cyclin D1, which jointly
mediate the regulation of cell cycle progression. The DNA damage
repair pathway regulates ATM, BRCA1, and NLRP3 to maintain genome
stability through coordinated damage sensing, repair, and
inflammatory responses. PRMT5, protein arginine methyltransferase
5; ATM, Ataxia-telangiectasia mutated; NLRP3, NLR family pyrin
domain containing 3; pRB, retinoblastoma protein.

Figure 3

Mechanisms and combination
therapeutic strategies of PRMT5 inhibitors in GI malignancies. HCC:
PRMT5 inhibitor (GSK591) combined with PD-L1 blockade reinforces
CD8+ T-cell antitumor immunity. CRC: PRMT5 inhibition
plus irinotecan induces a dMMR-like state and activates the
cGAS-STING pathway. ESCC: PRMT5 inhibitor (GSK3326595) combined
with radiotherapy inhibits DNA damage repair and induces
ferroptosis, reversing radio-resistance. PRMT5, protein arginine
methyltransferase 5; PD-L1, programmed cell death-ligand 1; HCC,
hepatocellular carcinoma; CRC, colorectal cancer; ESCC, esophageal
squamous cell carcinoma; cGAS-STING, cGMP-AMP synthase-stimulator
of interferon genes; dMMR, deficient mismatch repair; MTAP,
methylthioadenosine phosphorylase; MSS, microsatellite stable; GI,
gastrointestinal; IR, ionizing radiation.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang R, Lu Y, Fang X, Zhang F, Wu W, Song J and Liang Z: Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review). Oncol Lett 31: 258, 2026.
APA
Zhang, R., Lu, Y., Fang, X., Zhang, F., Wu, W., Song, J., & Liang, Z. (2026). Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review). Oncology Letters, 31, 258. https://doi.org/10.3892/ol.2026.15613
MLA
Zhang, R., Lu, Y., Fang, X., Zhang, F., Wu, W., Song, J., Liang, Z."Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review)". Oncology Letters 31.6 (2026): 258.
Chicago
Zhang, R., Lu, Y., Fang, X., Zhang, F., Wu, W., Song, J., Liang, Z."Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review)". Oncology Letters 31, no. 6 (2026): 258. https://doi.org/10.3892/ol.2026.15613
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang R, Lu Y, Fang X, Zhang F, Wu W, Song J and Liang Z: Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review). Oncol Lett 31: 258, 2026.
APA
Zhang, R., Lu, Y., Fang, X., Zhang, F., Wu, W., Song, J., & Liang, Z. (2026). Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review). Oncology Letters, 31, 258. https://doi.org/10.3892/ol.2026.15613
MLA
Zhang, R., Lu, Y., Fang, X., Zhang, F., Wu, W., Song, J., Liang, Z."Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review)". Oncology Letters 31.6 (2026): 258.
Chicago
Zhang, R., Lu, Y., Fang, X., Zhang, F., Wu, W., Song, J., Liang, Z."Emerging role of protein arginine methyltransferase 5 in gastrointestinal cancer (Review)". Oncology Letters 31, no. 6 (2026): 258. https://doi.org/10.3892/ol.2026.15613
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