Editors' ChoiceFibrosis

Vitamin D–mediated cancer therapy needs p62

Sci. Signal.  18 Oct 2016:
Vol. 9, Issue 450, pp. ec244
DOI: 10.1126/scisignal.aal2036

Patients with intermediate- or advanced-stage hepatocellular carcinoma (HCC) have no effective treatment options. Chronic inflammation and fibrosis are hallmarks of HCC. Vitamin D has an antifibrotic effect in the liver by suppressing the production of collagen in stromal hepatic stellate cells (HSCs), thus dietary vitamin D supplementation may be a therapeutic strategy to combat HCC progression or the associated loss of liver function. Findings from Duran et al. in mice caution that this approach may not be effective in patients that have a deficiency in the autophagy-associated adaptor protein p62 in their HSCs. The abundance of p62 is increased in HCC cells; whether this is a tumor-promoting effect is unknown. In prostate cancer models, p62 in the stromal cells may be tumor suppressive. Global or HSC-specific knockout of p62 promoted liver inflammation, fibrosis, and tumor growth in a carcinogen- and high-fat diet–induced mouse model of HCC, and knockdown of p62 in cultured human HSCs induced the abundance of a stellate cell activation marker and the expression of the gene encoding collagen I. The vitamin D analog calcipotriol induced a quiescent state in cultured HSCs, but p62 knockdown prevented this effect of vitamin D. Analysis of mouse and human tissue revealed that the abundance of p62 was lower in HSCs from mice or patients with HCC than in those from healthy controls and that the abundance of p62 was high in the tumor cells. Culturing HSCs in HCC-conditioned medium reduced the abundance of p62 at both the protein and mRNA levels. Upon activation, the vitamin D receptor (VDR) forms a heterodimer with the retinoid-X receptor α (RXRα) to regulate gene expression. Transcriptome analysis revealed that calcipotriol failed to increase the occupancy of the RXRα/VDR heterodimer at target promoters in p62-deficient HSCs. Interaction and mutational analyses revealed that p62 interacted with both RXRα and VDR and promoted heterodimer formation in response to calcipotriol to enable repression of the expression of fibrotic genes in HSCs. Calcipotriol attenuated the fibrotic effects of carcinogen in wild-type mice but had no significant effect in p62-deficient mice. Although further work is needed to fully understand the mechanisms of VDR signaling in the tumor context (see Hu and Zender), the findings suggest that clinical trials for vitamin D or VDR-activating agents in HCC may have better outcomes if patients were stratified on the basis of stellate cell p62 abundance.

A. Duran, E. D. Hernandez, M. Reina-Campos, E. A. Castilla, S. Subramaniam, S. Raghunandan, L. R. Roberts, T. Kisseleva, M. Karin, M. T. Diaz-Meco, J. Moscat, p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer. Cancer Cell 30, 595–609 (2016). [PubMed]

Z. Hu, L. Zender, p62 in liver disease: Good guy or bad guy? Cancer Cell 30, 509–510 (2016). [PubMed]

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