Protein arginine methylation as a regulator of hepatic cancer stemness and glucose metabolism

Abstract

Arginine methylation is a common post-translational modification that plays pivotal roles in signal transduction. However, its function in human diseases is poorly understood. In this study, we found protein arginine methyltransferase 6 (PRMT6) to be frequently down-regulated in hepatocellular carcinoma (HCC) and its expression to negatively correlate with aggressive cancer features in HCC patients. Silencing of PRMT6 promoted the tumor-initiating, metastasis, therapy resistance and glucose metabolism potential of HCC cell lines and patient-derived organoids; while overexpression of PRMT6 led to an opposing effect. Findings of our lentiviral based functional studies was further substantiated by PRMT6 wild-type and catalytic inactive methyltransferase mutant overexpression. Consistently, loss of PRMT6 expression aggravated liver tumorigenesis in chemical-induced HCC PRMT6 knockout mice. Contrary to its usual localization in the nucleus where it has previously been identified to play a role in histone modification in other tumor types, we did not find PRMT6 to alter the H3R2 mark in HCC cells. Interestingly, we identified a previously unappreciated role of PRMT6 in the cytoplasm. Integrated transcriptome and protein-protein interaction studies revealed an enrichment of genes implicated in RAS signaling and that PRMT6 interacted with CRAF on arginine 100 and as a result hindered its RAS binding potential and altered its downstream MEK/ ERK signaling. As a consequence, down-regulation of PRMT6 in HCC will result in activation of ERK-mediated cancer stemness via regulating CD133, SOX2 and NANOG, as well as ERKmediated glucose metabolic reprogramming via regulating PKM2.