title: ALDH2(E487K) mutation increases protein turnover and promotes murine hepatocarcinogenesis.
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.
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139; shengfang.jin@agios.com tmak@uhnres.utoronto.ca cangyong@zju.edu.cn.
authors.forename: Shengfang
authors.initials: S
authors.lastname: Jin
authors.affiliation: 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;
authors.forename: Jiang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Oncology Business Unit and Innovation Center for Cell Signaling Network, WuXi AppTec Co., Ltd., Shanghai 200131, China;
authors.forename: Lizao
authors.initials: L
authors.lastname: Chen
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
authors.forename: Gavin
authors.initials: G
authors.lastname: Histen
authors.affiliation: Oncology Business Unit and Innovation Center for Cell Signaling Network, WuXi AppTec Co., Ltd., Shanghai 200131, China;
authors.forename: Zhizhong
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
authors.forename: Stefan
authors.initials: S
authors.lastname: Gross
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Hixon
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
authors.forename: Charles
authors.initials: C
authors.lastname: Kung
authors.affiliation: Oncology Business Unit and Innovation Center for Cell Signaling Network, WuXi AppTec Co., Ltd., Shanghai 200131, China;
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Life Sciences Institute and Innovation Center for Cell Signaling Network, Zhejiang University, Hangzhou, Zhejiang 310058, China;
authors.forename: Yufei
authors.initials: Y
authors.lastname: Fu
authors.affiliation: Oncology Business Unit and Innovation Center for Cell Signaling Network, WuXi AppTec Co., Ltd., Shanghai 200131, China;
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of General Surgery, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China;
authors.forename: Xiujun
authors.initials: X
authors.lastname: Cai
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
authors.forename: Hua
authors.initials: H
authors.lastname: Yang
authors.affiliation: The Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, ON, Canada M5G 2C1.
authors.forename: Rob A
authors.initials: RA
authors.lastname: Cairns
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
authors.forename: Marion
authors.initials: M
authors.lastname: Dorsch
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
authors.forename: Shinsan M
authors.initials: SM
authors.lastname: Su
authors.affiliation: Agios Pharmaceuticals, Inc., Cambridge, MA 02139;
authors.forename: Scott
authors.initials: S
authors.lastname: Biller
authors.affiliation: 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.
authors.forename: Tak W
authors.initials: TW
authors.lastname: Mak
authors.affiliation: 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.
authors.forename: Yong
authors.initials: Y
authors.lastname: Cang
mesh_terms: D000435:Alcoholic Intoxication / Q000201:enzymology / Q000473:pathology; D000444:Aldehyde Dehydrogenase / Q000235:genetics*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D063646:Carcinogenesis / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000431:Ethanol / Q000009:adverse effects; D055879:Gene Knock-In Techniques; D060005:Genotyping Techniques; D022781:Hepatocytes / Q000201:enzymology / Q000473:pathology; D006801:Humans; D017495:Hyperpigmentation / Q000473:pathology; D007150:Immunohistochemistry; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008113:Liver Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D008810:Mice, Inbred C57BL; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D011110:Polymorphism, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D012867:Skin / Q000473:pathology; D016019:Survival Analysis
chemical_list: D050505:Mutant Proteins; D000431:Ethanol; C096127:ALDH2 protein, human; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D046988:Proteasome Endopeptidase Complex
keywords: ALDH2*2 polymorphism; Asian flush; alcohol metabolism; liver cancer; mouse model