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Cancer Cell. 2016 Oct 10;30(4):595-609. doi: 10.1016/j.ccell.2016.09.004.

p62/SQSTM1 by Binding to Vitamin D Receptor Inhibits Hepatic Stellate Cell Activity, Fibrosis, and Liver Cancer.

Author information

1
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
2
Sanford Burnham Prebys Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
3
Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.
4
Department of Bioengineering, Department of Cellular and Molecular Medicine, and Department of Chemistry and Biochemistry, Departments of Pharmacology and Pathology, Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA.
5
Department of Surgery, Departments of Pharmacology and Pathology, Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA.
6
Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, Moores Cancer Center, UCSD School of Medicine, La Jolla, CA 92093-0723, USA.
#
Contributed equally

Abstract

Hepatic stellate cells (HSCs) play critical roles in liver fibrosis and hepatocellular carcinoma (HCC). Vitamin D receptor (VDR) activation in HSCs inhibits liver inflammation and fibrosis. We found that p62/SQSTM1, a protein upregulated in liver parenchymal cells but downregulated in HCC-associated HSCs, negatively controls HSC activation. Total body or HSC-specific p62 ablation potentiates HSCs and enhances inflammation, fibrosis, and HCC progression. p62 directly interacts with VDR and RXR promoting their heterodimerization, which is critical for VDR:RXR target gene recruitment. Loss of p62 in HSCs impairs the repression of fibrosis and inflammation by VDR agonists. This demonstrates that p62 is a negative regulator of liver inflammation and fibrosis through its ability to promote VDR signaling in HSCs, whose activation supports HCC.

KEYWORDS:

fibrosis; hepatic stellate cells; hepatocellular carcinoma; inflammation; liver cancer; non-alcoholic steatohepatitis; nuclear receptors; p62; sequestosome-1; vitamin D receptor

Comment in

PMID:
27728806
PMCID:
PMC5081228
DOI:
10.1016/j.ccell.2016.09.004
[Indexed for MEDLINE]
Free PMC Article

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