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

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. H2 O2 -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.

Regulation of autophagy by protein methylation and acetylation in cancer.

Autophagy is a highly conserved mechanism responsible for cellular homeostasis and integrity in a variety of physiological conditions. Materials targeted for degradation are directed to autophagosomes and autolysosomes, where they are broken down into their base components. Aberrant regulation of autophagy is significantly associated with various cancers and neurodegenerative diseases. Recently, accumulating evidence has revealed that the coordinated regulation of histone and non-histone protein modification is associated with autophagy. In this review, we highlight the recent progress that has been made in elucidating the molecular basis of protein methylation and acetylation associated with autophagy at the transcriptional and posttranslational levels. Furthermore, we discuss the importance of describing causality between protein methylation/acetylation and autophagy regulation as compelling therapeutic opportunities in cancer pathogenesis and progression.