An unexpected tumor suppressor role of SQSTM1/p62 in liver tumorigenesis

Abstract

ABSTRACT SQSTM1/p62 (sequestosome 1) is a macroautophagy/autophagy receptor protein that is degraded by selective autophagy. Intracellular accumulation of SQSTM1 activates multiple cell survival signaling pathways including NFΚB/NF-κB (nuclear factor kappa B), MTOR (mechanistic target of rapamycin kinase) and NFE2L2/Nrf2 (nuclear factor, erythroid derived 2, like 2). Both SQSTM1 and NFE2L2 have been considered as oncogenic, and increased accumulation of SQSTM1 and NFE2L2 activation have been frequently observed in various cancers including hepatocellular carcinoma. In a recent study, we found that deletion of Sqstm1 improved hepatic metabolic reprogramming and cell repopulation resulting in the attenuation of liver injury in mice with liver-specific deletion of Atg5 and Tsc1 that have defective hepatic autophagy and persistent MTOR complex 1 (MTORC1) activation. To our surprise, hepatocytic deletion of Sqstm1 promotes liver tumorigenesis in liver-specific atg5 and tsc1 double-knockout mice. Overall, these findings reveal a complex interplay among autophagy, SQSTM1 and MTORC1 and their differential roles either as oncogenic or tumor suppressor in liver tumorigenesis depending on the disease stage and context.