An unexpected tumor suppressor role of SQSTM1/p62 in liver tumorigenesis
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Published on: July 22, 2020
Xiaojuan Chao1, Hong-Min Ni1, Wen-Xing Ding1
1Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, Kansas City, KS USA.
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.
Insights
Deletion of SQSTM1/p62 protein surprisingly promoted liver tumorigenesis in mice with defective autophagy. This highlights the complex, context-dependent roles of SQSTM1 and autophagy in liver cancer progression.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- SQSTM1/p62 is an autophagy receptor degraded by selective autophagy.
- Accumulation of SQSTM1 activates cell survival pathways (NF-κB, MTOR, Nrf2).
- SQSTM1 and Nrf2 are implicated in various cancers, including hepatocellular carcinoma.
Purpose of the Study:
- To investigate the role of SQSTM1 in liver injury and tumorigenesis.
- To explore the interplay between autophagy, SQSTM1, and MTORC1 signaling in the liver.
Main Methods:
- Utilized mouse models with liver-specific deletion of Atg5 and Tsc1 to induce defective autophagy and MTORC1 activation.
- Generated hepatocyte-specific Sqstm1 knockout mice in the context of autophagy deficiency.
Main Results:
- Deletion of Sqstm1 attenuated liver injury by improving metabolic reprogramming and cell repopulation in autophagy-deficient mice.
- Unexpectedly, hepatocytic deletion of Sqstm1 promoted liver tumorigenesis in mice with defective hepatic autophagy and MTORC1 activation.
Conclusions:
- SQSTM1 plays a dual role in liver tumorigenesis, acting as a tumor suppressor in certain contexts and potentially oncogenic in others.
- Findings reveal a complex interplay between autophagy, SQSTM1, and MTORC1, influencing liver disease progression and cancer development.
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