Epigenetic alterations represent heritable yet reversible structural changes in histone or DNA. Protein arginine methylation, a common post-translational modification, is mediated by the protein arginine methyltransferase (PRMT) family. These proteins serve as “writers”, catalyzing the transfer of methyl groups from S-adenosylmethionine (SAM) to arginine residues on both histone and nonhistone proteins, leading to changes in protein–protein/RNA interactions, gene expression, and protein translation.

Of these, PRMT5, a primary type II methyltransferase that catalyzes the symmetric demethylation of arginine residues in both histone and nonhistone proteins, is increasingly implicated in tumorigenesis and therapeutic resistance in multiple malignancies. A recent review published in the Genes & Diseases journal by researchers from Westlake University, the Key Laboratory of Integrated Traditional Chinese and Western Medicine for Biliary and Pancreatic Diseases of Zhejiang Province, Hangzhou Institute of Digestive Diseases, and the Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, explored the critical role of PRMT5 in tumorigenesis and tumor immunology and as a therapeutic target in various solid tumors.

The review begins with a brief introduction on the different types of PRMTs, their functions, and a summary of the interactions between PRMT5 and other genes. It then explores how PRMT5 promotes the proliferation, metastasis, therapy resistance, and an immunosuppressive tumor microenvironment in various solid malignancies, such as lung cancer, glioblastoma, breast cancer, colorectal cancer, melanoma, esophageal squamous cell carcinoma, prostate cancer, cervical cancer, and pancreatic cancer.

The review then summarizes the therapeutic implications of targeting PRMT5 in these cancers. PRMT5 inhibitors such as PF-06939999, JNJ-64619178, MRTX1719, and EPZ015666 have demonstrated remarkable therapeutic effects in lung cancer. Similarly, JNJ-64619178 and EPZ015666, along with small-molecular inhibitors targeting PRMT5, have exhibited potent anti-glioblastoma effects. PRMT5 inhibition mitigated CDK4/6 inhibitor-resistant ER-positive/RB-deficient breast cancer. Similar therapeutic benefits have been observed in ovarian, colorectal, and pancreatic cancers.

PRMT5-mediated gene expression may exhibit either synergy or antagonism with other methyltransferases, and is a major factor limiting the clinical translation of PRMT5 inhibitors. Therefore, a comprehensive understanding of PRMT5 regulation, including its epigenetic regulation, transcriptional control, RNA transport, protein stability, and posttranslational modifications, may help realize the clinical translation of PRMT5 inhibitors.

In conclusion, the authors present a critical evaluation of the role of PRMT5 in various solid malignancies and describe the potential anti-cancer implications of PRMT5 inhibition.


Reference
Title of the original paper: Protein arginine methyltransferase 5 as a novel therapeutic target in solid tumors

Journal: Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101796


Funding Information:

• Zhejiang Provincial Foundation of Natural Science (China) (No. LQ23H160046)
• National Natural Science Foundation of China (No. 82202876)
• Medical and Health Research Project of Zhejiang Province, China (No. 2023RC225)

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