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Hepatology. 2018 May;67(5):1823-1841. doi: 10.1002/hep.29663. Epub 2018 Apr 1.

High mobility group protein B1 controls liver cancer initiation through yes-associated protein -dependent aerobic glycolysis.

Author information

1
Third Affiliated Hospital, Center for DAMP Biology, Key Laboratory for Major Obstetric Diseases of Guangdong Province, Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Protein Modification and Degradation Laboratory, Guangzhou Medical University, Guangzhou, China.
2
Department of Infectious Diseases and State Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China.
3
Laboratory of Emergency Medicine, North Shore University Hospital, Manhasset, NY.
4
Feinstein Institute for Medical Research, Manhasset, NY.
5
Department of Surgery, University of Pittsburgh, Pittsburgh, PA.

Abstract

Emerging studies have suggested that the Hippo pathway is involved in the tumorigenesis of hepatocellular carcinoma (HCC). However, the key regulator of the Hippo pathway in liver tumor metabolic reprogramming remains elusive. Here, we provide evidence that high mobility group box 1 (HMGB1), a chromosomal protein, plays a role in the regulation of the Hippo pathway during liver tumorigenesis. Cre/loxP recombination-mediated HMGB1 depletion in hepatocytes blocks diethylnitrosamine-induced liver cancer initiation in mice, whereas short hairpin RNA-mediated gene silencing of HMGB1 inhibits HCC cell proliferation. Mechanistically, the binding of HMGB1 to GA-binding protein alpha promotes the expression of yes-associated protein (YAP), a major downstream effector of the Hippo pathway that contributes to liver tumorigenesis by inducing hypoxia-inducible factor 1α (HIF1α)-dependent aerobic glycolysis. Like wild-type YAP-complementary DNA, YAP-5SA-S94A can restore HIF1α DNA binding activity, glycolysis-associated gene expression, and HIF1α-YAP complex formation in YAP-knockdown HCC cell lines. In contrast, verteporfin, a reagent targeting the interface between YAP and TEA domain transcription factor, has the ability to block YAP-HIF1α complex formation. Notably, genetic or pharmacologic inhibition of the HMGB1-YAP-HIF1α pathway confers protection against excessive glycolysis and tumor growth in mice.

CONCLUSION:

These findings demonstrate that HMGB1 plays a novel role in modulating the YAP-dependent HIF1α pathway and shed light on the development of metabolism-targeting therapeutics for HCC chemoprevention. (Hepatology 2018;67:1823-1841).

PMID:
29149457
PMCID:
PMC5906197
DOI:
10.1002/hep.29663
[Indexed for MEDLINE]
Free PMC Article

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