CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma

Zhao-Qing Shen; Yi-Fan Chen; Jim-Ray Chen; Yuh-Shan Jou; Pei-Chun Wu; Cheng-Heng Kao; Chih-Hao Wang; Yi-Long Huang; Chian-Feng Chen; Ting-Shuo Huang; Yu-Chiau Shyu; Shih-Feng Tsai; Lung-Sen Kao; Ting-Fen Tsai

doi:10.1016/j.celrep.2017.10.099

CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma

Cell Rep. 2017 Nov 21;21(8):2198-2211. doi: 10.1016/j.celrep.2017.10.099.

Authors

Zhao-Qing Shen¹, Yi-Fan Chen², Jim-Ray Chen³, Yuh-Shan Jou⁴, Pei-Chun Wu⁵, Cheng-Heng Kao⁶, Chih-Hao Wang⁷, Yi-Long Huang¹, Chian-Feng Chen⁸, Ting-Shuo Huang⁹, Yu-Chiau Shyu¹⁰, Shih-Feng Tsai¹¹, Lung-Sen Kao¹², Ting-Fen Tsai¹³

Affiliations

¹ Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan.
² The Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, Taiwan.
³ Department of Pathology, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan.
⁴ Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan.
⁵ Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.
⁶ Center of General Education, Chang Gung University, Taoyuan 333, Taiwan.
⁷ Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
⁸ Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan.
⁹ Department of General Surgery, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan.
¹⁰ Community Medicine Research Center, Chang Gung Memorial Hospital, Keelung Branch, Keelung 204, Taiwan.
¹¹ Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan; Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
¹² Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan; Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan.
¹³ Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei 112, Taiwan; Brain Research Center, National Yang-Ming University, Taipei 112, Taiwan; Aging and Health Research Center, National Yang-Ming University, Taipei 112, Taiwan; Genome Research Center, National Yang-Ming University, Taipei 112, Taiwan; Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 350, Taiwan. Electronic address: tftsai@ym.edu.tw.

PMID: 29166610
DOI: 10.1016/j.celrep.2017.10.099

Abstract

CISD2 is located within the chromosome 4q region frequently deleted in hepatocellular carcinoma (HCC). Mice with Cisd2 heterozygous deficiency develop a phenotype similar to the clinical manifestation of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). Cisd2 haploinsufficiency causes a low incidence (20%) of spontaneous HCC and promotes HBV-associated and DEN-induced HCC; conversely, 2-fold overexpression of Cisd2 suppresses HCC in these models. Mechanistically, Cisd2 interacts with Serca2b and mediates its Ca²⁺ pump activity via modulation of Serca2b oxidative modification, which regulates ER Ca²⁺ uptake and maintains intracellular Ca²⁺ homeostasis in the hepatocyte. CISD2 haploinsufficiency disrupts calcium homeostasis, causing ER stress and subsequent NAFLD and NASH. Hemizygous deletion and decreased expression of CISD2 are detectable in a substantial fraction of human HCC specimens. These findings substantiate CISD2 as a haploinsufficient tumor suppressor and highlights Cisd2 as a drug target when developing therapies to treat NAFLD/NASH and prevent HCC.

Keywords: CISD2; ER stress; Serca2b; calcium homeostasis; haploinsufficiency; hepatocellular carcinoma; nonalcoholic fatty liver disease; tumor suppressor gene.

MeSH terms

Animals
Autophagy-Related Proteins
Calcium / metabolism*
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology*
Carrier Proteins / genetics
Carrier Proteins / metabolism*
Haploinsufficiency / genetics*
Homeostasis / physiology
Humans
Liver Neoplasms / genetics
Liver Neoplasms / pathology*
Membrane Proteins / genetics
Membrane Proteins / metabolism*
Mice
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Non-alcoholic Fatty Liver Disease / metabolism
Non-alcoholic Fatty Liver Disease / pathology

Substances

Autophagy-Related Proteins
CISD2 protein, human
Carrier Proteins
Membrane Proteins
Nerve Tissue Proteins
Noxp70 protein, mouse
Calcium