A review published in Genes & Diseases highlights the complex interplay between protein arginine methylation and ubiquitination, two forms of protein modification that can profoundly influence cancer development, progression and treatment response. The article brings together current understanding of how these interconnected molecular processes regulate proteins involved in cancer and identifies opportunities for future therapeutic approaches.

Protein arginine methyltransferases (PRMTs) modify arginine residues in histone and nonhistone proteins, influencing protein activity, interactions and cellular functions. Ubiquitination, meanwhile, can control the stability and activity of proteins by attaching ubiquitin molecules to selected targets. Rather than operating independently, these systems form a dynamic, bidirectional network in which methylation can alter ubiquitination and protein degradation, while ubiquitination can regulate the stability and activity of PRMT enzymes.

This methylation–ubiquitination crosstalk is connected with numerous processes central to cancer, including tumor invasion and metastasis, cell proliferation, apoptosis, ferroptosis, DNA repair and genomic stability, metabolic reprogramming, drug resistance and immune escape. By changing whether important proteins are stabilized or degraded, the network can influence signaling pathways that determine how cancer cells grow, survive, spread and respond to treatment.

PRMT enzymes can, for example, modify target proteins in ways that reduce their recognition by ubiquitin ligases, helping those proteins avoid degradation. In other circumstances, methylation can encourage ubiquitination and accelerate protein removal. The relationship also works in reverse: E3 ubiquitin ligases and deubiquitinases can alter the stability of PRMTs themselves, creating an intricate system of molecular feedback.

These mechanisms may have important implications for cancer therapy. Targeting enzymes involved in both pathways could offer new ways to address treatment resistance and influence immune responses. Potential future directions include dual-function inhibitors, small-molecule degraders and engineered nanobodies, alongside strategies combining modulation of these pathways with immune checkpoint blockade. However, challenges remain, including the highly context-dependent nature of the molecular network and the need for greater precision when targeting it therapeutically.
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
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Reference
Jiawen Zhou, Ao Zhang, Jiuling Zhu, Fei Tang, Ziyang Yuan, Wenlong Ma, Qi Wang, Jun Lu, Shu Li, Zhongwei Li, Protein arginine methylation and ubiquitination: A prominent crosstalk and its functions in cancer, Genes & Diseases, Volume 13, Issue 6, 2026, 101997, https://doi.org/10.1016/j.gendis.2025.101997
Funding
Nature Science Foundation of Jiangsu Province, China 82173060
Nature Science Foundation of Jiangsu Province, China 82573790
Outstanding Youth Project of the University Natural Science Research in Anhui Province, China 2024AH020013
Key Project of the University Natural Science Research in Anhui Province, China 2023AH051774
Launch Foundation for High Level Talent Research of Wannan Medical University (China) WYRCQD2024011
Wannan Medical University Doctoral Research Startup Fund (China) WYRCQD2022005
Wannan Medical University Student Research Grant (China) WK2024XS58