title: A single non-synonymous NCOA5 variation in type 2 diabetic patients with hepatocellular carcinoma impairs the function of NCOA5 in cell cycle regulation.
abstract: Type 2 Diabetes (T2D) is a risk factor for hepatocellular carcinoma (HCC). We have previously described that haploinsufficiency of nuclear receptor coactivator 5 (NCOA5) is a genetic defect linking glucose intolerance to HCC. Here we report identification and characterization of a single nucleotide variation (T445A) in NCOA5, causing an amino acid Thr to Ala substitution, in adjacent non-tumorous liver tissues derived from patients with concurrent HCC and T2D. By using Tet-On inducible expression cells, we show that ectopic expression of NCOA5wt suppressed proliferation of HCC cells via induction of G2/M arrest, while ectopic expression of NCOA5T445A had a significantly lesser effect compared to ectopic expression of NCOA5wt. Furthermore, ectopic expression of NCOA5wt increased the occurrence of DNA damage and cell senescence, whereas expression of NCOA5T445A partly lost this activity. Xenograft tumor model analysis demonstrated that ectopic NCOA5wt expression reduced HCC tumor growth and the T445A variation impairs its tumor growth inhibitory function. Collectively, our data show that the T445A variation impairs the ability of NCOA5 to inhibit growth of HCC, suggesting that this variation may have potential to increase susceptibility to HCC comorbid with T2D.
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong, 510315, China; Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, 510315, China.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong, 510315, China; Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, 510315, China.
authors.forename: Feiye
authors.initials: F
authors.lastname: Liu
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: Shenglan
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: Jake
authors.initials: J
authors.lastname: Reske
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong, 510315, China; Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, 510315, China.
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114, USA.
authors.forename: Chin-Lee
authors.initials: CL
authors.lastname: Wu
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA.
authors.forename: Chengfeng
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA; Cancer Center, Southern Medical University, Guangzhou, Guangdong, 510315, China; Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, 510315, China.
authors.forename: Fengsheng
authors.initials: F
authors.lastname: Chen
authors.affiliation: Cancer Center, Southern Medical University, Guangzhou, Guangdong, 510315, China; Traditional Chinese Medicine-Integrated Hospital, Southern Medical University, Guangzhou, Guangdong, 510315, China. Electronic address: luorc01@163.com.
authors.forename: Rongcheng
authors.initials: R
authors.lastname: Luo
authors.affiliation: Department of Physiology, Michigan State University, East Lansing, MI, 48824, USA. Electronic address: xiaoh@msu.edu.
authors.forename: Hua
authors.initials: H
authors.lastname: Xiao
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D059447:Cell Cycle Checkpoints; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D056918:Nuclear Receptor Coactivators / Q000235:genetics* / Q000378:metabolism; D014162:Transfection
chemical_list: C418222:NCOA5 protein, human; D056918:Nuclear Receptor Coactivators
keywords: Hepatocellular carcinoma; NCOA5; SNV; Tumor suppressor; Type 2 diabetes