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Papers of the Week

2022 Sep 17

Cancer Sci

ROS inhibits RORα degradation by decreasing its arginine methylation in liver cancer.


Im H, Baek H-J, Yang E, Kim K, Oh S K, Lee J-S, Kim H K, Lee J M
Cancer Sci. 2022 Sep 17.
PMID: 36114756.


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 cause RORα remain largely unknown, especially in liver cancer. Arginine methylation is a common PTM in arginine residues of non- and histone proteins and affects substrate protein function and fate. We found a conserved amino acid sequence, including R37 in the RORα N-terminus compared to histone H3. 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. H O -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.