Cancer Cell
Volume 30, Issue 4, 10 October 2016, Pages 595-609
Journal home page for Cancer Cell

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

https://doi.org/10.1016/j.ccell.2016.09.004Get rights and content
Under an Elsevier user license
open archive

Highlights

  • p62 levels are reduced in hepatic stellate cells (HSCs) in human HCC samples

  • Loss of p62 in HSCs results in increased fibrosis, inflammation, and HCC

  • p62 is critical for VDR:RXR heterodimerization and inhibition of HSC activation

  • Enhanced HSC activation by p62 loss impairs VDR signaling and promotes HCC

Summary

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

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

Cited by (0)

7

Co-first author

8

Lead Contact