Retinoic acid receptor–related orphan receptor α (RORα) is a transcription factor involved in nuclear gene expression and a known tumor suppressor. RORα was the first identified substrate of lysine methylation–dependent degradation. However, the mechanisms of other post-translational modifications (PTMs) that occur in RORα remain largely unknown, especially in liver cancer. Arginine methylation is a common PTM in arginine residues of nonhistone and histone proteins and affects substrate protein function and fate. We found an analogous amino acid disposition containing R37 at the ROR N-terminus compared to histone H3 residue, which is arginine methylated. Here, we provide evidence that R37 methylation–dependent degradation is carried out by protein arginine methyltransferase 5 (PRMT5). Further, we discovered that PRMT5 regulated the interaction between the E3 ubiquitin ligase ITCH and RORα through RORα arginine methylation. Arginine methylation–dependent ubiquitination-mediated RORα degradation reduced downstream target gene activation. H2O2-induced reactive oxygen species (ROS) decreased PRMT5 protein levels, consequently increasing RORα protein levels in HepG2 liver cancer cells. In addition, ROS inhibited liver cancer progression by inducing apoptosis via PRMT5-mediated RORα methylation and the ITCH axis. Our results potentiate PRMT5 as an elimination target in cancer therapy, and this additional regulatory level within ROS signaling may help identify new targets for therapeutic intervention in liver cancer.
Bibliographical noteFunding Information:
CMV10-RORα and p21 luciferase constructs were kindly gifted by Sung Hee Baek from Seoul National University.
This work was supported by the Basic Science Research Program (NRF‐2021R1C1C1008780 to J.M.L. and NRF‐2020R1C1C1010489 to H.K.) from the National Research Foundation (NRF) grant funded by the Korea government.
© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
- arginine methylation
- liver cancer
ASJC Scopus subject areas
- Cancer Research