A single non-synonymous NCOA5 variation in type 2 diabetic patients with hepatocellular carcinoma impairs the function of NCOA5 in cell cycle regulation

Xinhui Liu; Feiye Liu; Shenglan Gao; Jake Reske; Aimin Li; Chin Lee Wu; Chengfeng Yang; Fengsheng Chen; Rongcheng Luo; Hua Xiao

doi:10.1016/j.canlet.2017.01.028

A single non-synonymous NCOA5 variation in type 2 diabetic patients with hepatocellular carcinoma impairs the function of NCOA5 in cell cycle regulation

Xinhui Liu, Feiye Liu, Shenglan Gao, Jake Reske, Aimin Li, Chin Lee Wu, Chengfeng Yang, Fengsheng Chen, Rongcheng Luo, Hua Xiao

Markey Cancer Center / Cancer Research Priority Initiative

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Pages (from-to)	152-161
Number of pages	10
Journal	Cancer Letters
Volume	391
DOIs	https://doi.org/10.1016/j.canlet.2017.01.028
State	Published - Apr 10 2017

Bibliographical note

Funding Information:
The authors thank members of the H.X. lab for helpful discussions. This work was supported by National Cancer Institute (R01 CA188305) to H. Xiao, and the Joint Research Fund for Overseas Chinese, Hong Kong and Macao Scientists of the National Natural Science Foundation of China (Grant No. 81428017) to R. Luo. X. Liu and F. Liu were supported in part by fellowships from Southern Medical University, China. F. Chen was supported in part by Youth Fund of the National Natural Science Foundation of China (Grant No. 81502378). C. Yang was supported by National Institute of Health (1R01ES017777-01).

Publisher Copyright:
© 2017 The Author(s)

Keywords

Hepatocellular carcinoma
NCOA5
SNV
Tumor suppressor
Type 2 diabetes

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.canlet.2017.01.028

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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.",

keywords = "Hepatocellular carcinoma, NCOA5, SNV, Tumor suppressor, Type 2 diabetes",

author = "Xinhui Liu and Feiye Liu and Shenglan Gao and Jake Reske and Aimin Li and Wu, {Chin Lee} and Chengfeng Yang and Fengsheng Chen and Rongcheng Luo and Hua Xiao",

note = "Funding Information: The authors thank members of the H.X. lab for helpful discussions. This work was supported by National Cancer Institute (R01 CA188305) to H. Xiao, and the Joint Research Fund for Overseas Chinese, Hong Kong and Macao Scientists of the National Natural Science Foundation of China (Grant No. 81428017) to R. Luo. X. Liu and F. Liu were supported in part by fellowships from Southern Medical University, China. F. Chen was supported in part by Youth Fund of the National Natural Science Foundation of China (Grant No. 81502378). C. Yang was supported by National Institute of Health (1R01ES017777-01). Publisher Copyright: {\textcopyright} 2017 The Author(s)",

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AU - Liu, Xinhui

AU - Liu, Feiye

AU - Gao, Shenglan

AU - Reske, Jake

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AU - Wu, Chin Lee

AU - Yang, Chengfeng

AU - Chen, Fengsheng

AU - Luo, Rongcheng

AU - Xiao, Hua

N1 - Funding Information: The authors thank members of the H.X. lab for helpful discussions. This work was supported by National Cancer Institute (R01 CA188305) to H. Xiao, and the Joint Research Fund for Overseas Chinese, Hong Kong and Macao Scientists of the National Natural Science Foundation of China (Grant No. 81428017) to R. Luo. X. Liu and F. Liu were supported in part by fellowships from Southern Medical University, China. F. Chen was supported in part by Youth Fund of the National Natural Science Foundation of China (Grant No. 81502378). C. Yang was supported by National Institute of Health (1R01ES017777-01). Publisher Copyright: © 2017 The Author(s)

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N2 - 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.

AB - 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.

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KW - NCOA5

KW - SNV

KW - Tumor suppressor

KW - Type 2 diabetes

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A single non-synonymous NCOA5 variation in type 2 diabetic patients with hepatocellular carcinoma impairs the function of NCOA5 in cell cycle regulation

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

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