Nov 18, 2017

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

Hepatology : Official Journal of the American Association for the Study of Liver Diseases
Ruochan ChenDaolin Tang

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 ...Continue Reading

  • References30
  • Citations9

References

Mentioned in this Paper

Metabolic Process, Cellular
Study
Biochemical Pathway
Gene Expression Regulation, Neoplastic
HMGB1 gene
Gene Knockdown Techniques
Diethylnitrosamine
Regulation of Biological Process
Endothelial PAS domain-containing protein 1
Liver Carcinoma

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