title: Inhibiting histone deacetylases suppresses glucose metabolism and hepatocellular carcinoma growth by restoring FBP1 expression.
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.
authors.affiliation: Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China.|Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.|Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, 213003, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Jin
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Yuqian
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China.|Jiangsu Engineering Research Center for Tumor Immunotherapy, Changzhou, Jiangsu, 213003, China.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Pan
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN, USA.
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.|Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA.
authors.forename: Haojie
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Tumor Biological Treatment, The Third Affiliated Hospital of Soochow University, 185 Juqian Street, Changzhou, 213003, China.
authors.forename: Jingting
authors.initials: J
authors.lastname: Jiang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D045744:Cell Line, Tumor; D005260:Female; D006597:Fructose-Bisphosphatase / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D056945:Hep G2 Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008875:Middle Aged; D034622:RNA Interference; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D056572:Histone Deacetylase Inhibitors; D006597:Fructose-Bisphosphatase; D006655:Histone Deacetylases; D005947:Glucose