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Proc Natl Acad Sci U S A. 2015 Jul 21;112(29):9088-93. doi: 10.1073/pnas.1510757112. Epub 2015 Jul 6.

ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis.

Author information

1
Agios Pharmaceuticals, Inc., Cambridge, MA 02139; shengfang.jin@agios.com tmak@uhnres.utoronto.ca cangyong@zju.edu.cn.
2
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China; Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China;
3
Oncology Business Unit and Innovation Center for Cell Signaling Network, WuXi AppTec Co., Ltd., Shanghai 200131, China;
4
Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
5
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China;
6
Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China;
7
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, ON, Canada M5G 2C1.
8
The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, ON, Canada M5G 2C1 shengfang.jin@agios.com tmak@uhnres.utoronto.ca cangyong@zju.edu.cn.
9
Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China; Oncology Business Unit and Innovation Center for Cell Signaling Network, WuXi AppTec Co., Ltd., Shanghai 200131, China; shengfang.jin@agios.com tmak@uhnres.utoronto.ca cangyong@zju.edu.cn.

Abstract

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) in the liver removes toxic aldehydes including acetaldehyde, an intermediate of ethanol metabolism. Nearly 40% of East Asians inherit an inactive ALDH2*2 variant, which has a lysine-for-glutamate substitution at position 487 (E487K), and show a characteristic alcohol flush reaction after drinking and a higher risk for gastrointestinal cancers. Here we report the characterization of knockin mice in which the ALDH2(E487K) mutation is inserted into the endogenous murine Aldh2 locus. These mutants recapitulate essentially all human phenotypes including impaired clearance of acetaldehyde, increased sensitivity to acute or chronic alcohol-induced toxicity, and reduced ALDH2 expression due to a dominant-negative effect of the mutation. When treated with a chemical carcinogen, these mutants exhibit increased DNA damage response in hepatocytes, pronounced liver injury, and accelerated development of hepatocellular carcinoma (HCC). Importantly, ALDH2 protein levels are also significantly lower in patient HCC than in peritumor or normal liver tissues. Our results reveal that ALDH2 functions as a tumor suppressor by maintaining genomic stability in the liver, and the common human ALDH2 variant would present a significant risk factor for hepatocarcinogenesis. Our study suggests that the ALDH2*2 allele-alcohol interaction may be an even greater human public health hazard than previously appreciated.

KEYWORDS:

ALDH2*2 polymorphism; Asian flush; alcohol metabolism; liver cancer; mouse model

PMID:
26150517
PMCID:
PMC4517197
DOI:
10.1073/pnas.1510757112
[Indexed for MEDLINE]
Free PMC Article

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