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

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 improved hepatic metabolic reprogramming and cell repopulation resulting in the attenuation of liver injury in mice with liver-specific deletion of and that have defective hepatic autophagy and persistent MTOR complex 1 (MTORC1) activation. To our surprise, hepatocytic deletion of promotes liver tumorigenesis in liver-specific and 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.