Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression

Jing Yang, Xin Jin, Yuqian Yan, Yingjie Shao, Yunqian Pan, Lewis Rowland Roberts, Jun Zhang, Haojie Huang, Jingting Jiang

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Abstract

Hepatocellular carcinoma (HCC) is one of the most commonly diagnosed cancers in the world. Elevated glucose metabolism in the availability of oxygen, a phenomenon called the Warburg effect, is important for cancer cell growth. Fructose-1,6-bisphosphatase (FBP1) is a rate-limiting enzyme in gluconeogenesis and is frequently lost in various types of cancer. Here, we demonstrated that expression of FBP1 was downregulated in HCC patient specimens and decreased expression of FBP1 associated with poor prognosis. Low expression of FBP1 correlated with high levels of histone deacetylase 1 (HDAC1) and HDAC2 proteins in HCC patient tissues. Treatment of HCC cells with HDAC inhibitors or knockdown of HDAC1 and/or HDAC2 restored FBP1 expression and inhibited HCC cell growth. HDAC-mediated suppression of FBP1 expression correlated with decreased histone H3 lysine 27 acetylation (H3K27Ac) in the FBP1 enhancer. Restored expression of FBP1 decreased glucose reduction and lactate secretion and inhibited HCC cell growth in vitro and tumor growth in mice. Our data reveal that loss of FBP1 due to histone deacetylation associates with poor prognosis of HCC and restored FBP1 expression by HDAC inhibitors suppresses HCC growth. Our findings suggest that repression of FBP1 by HDACs has important implications for HCC prognosis and treatment.

Original languageEnglish (US)
Article number43864
JournalScientific Reports
Volume7
DOIs
StatePublished - Mar 6 2017

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Histone Deacetylases
Hepatocellular Carcinoma
Glucose
Growth
Histone Deacetylase 1
Histone Deacetylase Inhibitors
Histones
Neoplasms
Fructose-Bisphosphatase
Gluconeogenesis
Acetylation
Lysine
Lactic Acid
Down-Regulation
Oxygen

ASJC Scopus subject areas

  • General

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Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression. / Yang, Jing; Jin, Xin; Yan, Yuqian; Shao, Yingjie; Pan, Yunqian; Roberts, Lewis Rowland; Zhang, Jun; Huang, Haojie; Jiang, Jingting.

In: Scientific Reports, Vol. 7, 43864, 06.03.2017.

Research output: Contribution to journalArticle

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AU - Jin, Xin

AU - Yan, Yuqian

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AU - Roberts, Lewis Rowland

AU - Zhang, Jun

AU - Huang, Haojie

AU - Jiang, Jingting

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