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

Ruochan Chen, Shan Zhu, Xue Gong Fan, Haichao Wang, Michael T. Lotze, Herbert J. Zeh, Timothy R. Billiar, Rui Kang, Daolin Tang

Research output: Contribution to journalArticle

15 Citations (Scopus)

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).

Original languageEnglish (US)
Pages (from-to)1823-1841
Number of pages19
JournalHepatology
Volume67
Issue number5
DOIs
StatePublished - May 2018
Externally publishedYes

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High Mobility Group Proteins
Glycolysis
Liver Neoplasms
Hypoxia-Inducible Factor 1
Hepatocellular Carcinoma
Carcinogenesis
Proteins
Liver
GA-Binding Protein Transcription Factor
Diethylnitrosamine
Chemoprevention
Gene Silencing
Gastroenterology
Small Interfering RNA
Genetic Recombination
Hepatocytes
Neoplasms
Transcription Factors
Complementary DNA
Cell Proliferation

ASJC Scopus subject areas

  • Hepatology

Cite this

High mobility group protein B1 controls liver cancer initiation through yes-associated protein -dependent aerobic glycolysis. / Chen, Ruochan; Zhu, Shan; Fan, Xue Gong; Wang, Haichao; Lotze, Michael T.; Zeh, Herbert J.; Billiar, Timothy R.; Kang, Rui; Tang, Daolin.

In: Hepatology, Vol. 67, No. 5, 05.2018, p. 1823-1841.

Research output: Contribution to journalArticle

Chen, Ruochan ; Zhu, Shan ; Fan, Xue Gong ; Wang, Haichao ; Lotze, Michael T. ; Zeh, Herbert J. ; Billiar, Timothy R. ; Kang, Rui ; Tang, Daolin. / High mobility group protein B1 controls liver cancer initiation through yes-associated protein -dependent aerobic glycolysis. In: Hepatology. 2018 ; Vol. 67, No. 5. pp. 1823-1841.
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AU - Wang, Haichao

AU - Lotze, Michael T.

AU - Zeh, Herbert J.

AU - Billiar, Timothy R.

AU - Kang, Rui

AU - Tang, Daolin

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AB - 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).

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