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

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11 Citations (Scopus)

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. Shen et al. demonstrate that CISD2 is a haploinsufficient 4q tumor suppressor in liver. Cisd2 haploinsufficiency causes nonalcoholic fatty liver disease and promotes hepatocellular carcinoma (HCC). Conversely, increase of Cisd2 suppresses HBV-associated and carcinogen-induced HCC. CISD2 may be a molecular target for HCC prevention.

Original languageEnglish
Pages (from-to)2198-2211
Number of pages14
JournalCell Reports
Volume21
Issue number8
DOIs
Publication statusPublished - Nov 21 2017

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Keywords

  • calcium homeostasis
  • CISD2
  • ER stress
  • haploinsufficiency
  • hepatocellular carcinoma
  • nonalcoholic fatty liver disease
  • Serca2b
  • tumor suppressor gene

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Shen, Z. Q., Chen, Y. F., Chen, J. R., Jou, Y. S., Wu, P. C., Kao, C. H., Wang, C. H., Huang, Y. L., Chen, C. F., Huang, T. S., Shyu, Y. C., Tsai, S. F., Kao, L. S., & Tsai, T. F. (2017). CISD2 Haploinsufficiency Disrupts Calcium Homeostasis, Causes Nonalcoholic Fatty Liver Disease, and Promotes Hepatocellular Carcinoma. Cell Reports, 21(8), 2198-2211. https://doi.org/10.1016/j.celrep.2017.10.099