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

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.