PRMT6 deficiency induces autophagy in hostile microenvironments of hepatocellular carcinoma tumors by regulating BAG5-associated HSC70 stability

Autophagy is a critical survival factor for cancer cells, whereby it maintains cellular homeostasis by degrading damaged organelles and unwanted proteins and supports cellular biosynthesis in response to stress. Cancer cells, including hepatocellular carcinoma (HCC), are often situated in a hypoxic, nutrient-deprived and stressful microenvironment where tumor cells are yet still able to adapt and survive. However, the mechanism underlying this adaptation and survival is not well-defined. We report deficiency of the post-translational modification enzyme protein arginine N-methyltransferase 6 (PRMT6) in HCC to promote the induction of autophagy under oxygen/nutrient-derived and sorafenib drug-induced stress conditions. Enhanced autophagic flux in HCC cells negatively correlated with PRMT6 expression, with the catalytic domain of PRMT6 critically important in mediating these autophagic activities. Mechanistically, PRMT6 physically interacts and methylates BAG5 to enhance the degradation of its interacting partner HSC70, a well-known autophagy player. The therapeutic potential of targeting BAG5 using genetic approach to reverse tumorigenicity and sorafenib resistance mediated by PRMT6 deficiency in HCC is also demonstrated in an in vivo model. The clinical implications of these findings are highlighted by the inverse correlative expressions of PRMT6 and HSC70 in HCC tissues. Collectively, deficiency of PRMT6 induces autophagy to promote tumorigenicity and cell survival in hostile microenvironments of HCC tumors by regulating BAG5-associated HSC70 stability through post-translational methylation of BAG5. Targeting BAG5 may therefore be an attractive strategy in HCC treatment by suppressing autophagy and inducing HCC cell sensitivity to sorafenib for treatment. PRMT6 deficiency induces autophagy to promote tumorigenicity and cell survival in hostile microenvironments of HCC tumors by regulating BAG5-associated HSC70 stability through post-translational methylation of BAG5 at arginine residues 15 and 24 on the N-terminus. [Display omitted] •PRMT6 plays a critical repressive role in maintenance of autophagy in HCC microenvironment.•HSC70 stability is epigenetically regulated by PRMT6 through site-specific arginine methylation of BAG5.•Targeting BA5 represents a novel approach to reverse PRMT6 deficiency-driven HCC.•PRMT6 is negatively correlated with HSC70 in HCC clinical samples.