High mobility group protein B1 controls liver cancer initiation through yes-associated protein -dependent aerobic glycolysis.
High mobility group protein B1 controls liver cancer initiation through yes-associated protein -dependent aerobic glycolysis.
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高迁移率族蛋白 B1 通过 yes 相关蛋白依赖性有氧糖酵解控制肝癌的发生
DOI：
10.1002/hep.29663
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发表时间：
2018-05
期刊：
影响因子：
--
通讯作者：
Tang D
中科院分区：
文献类型：
--
作者：
Chen R;Zhu S;Fan XG;Wang H;Lotze MT;Zeh HJ 3rd;Billiar TR;Kang R;Tang D
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 to support 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 shRNA-mediated gene silencing of HMGB1 inhibits HCC cell proliferation. Mechanistically, the binding of HMGB1 to GA-binding protein alpha (GABPα) promotes the expression of yes-associated protein (YAP), a major downstream effector of the Hippo pathway, which contributes to liver tumorigenesis by inducing hypoxia-inducible factor 1α (HIF1α)-dependent aerobic glycolysis. Like wild type YAP-cDNA, 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 (TEAD), has the ability to block YAP-HIF1α complex formation. Notably, genetic or pharmacological inhibition of the HMGB1-YAP-HIF1α pathway confers protection against excessive glycolysis and tumor growth in mice. Conclusion: These findings uncover that HMGB1 plays a novel role in modulating the YAP-dependent HIF1α pathway and sheds light on the development of metabolism-targeting therapeutics for HCC chemoprevention.
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