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

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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Shen ZQ,Chen YF,Chen JR,Jou YS,Wu PC,Kao CH,Wang CH,Huang YL,Chen CF,Huang TS,Shyu YC,Tsai SF,Kao LS,Tsai TF

doi

10.1016/j.celrep.2017.10.099

subject

Has Abstract

pub_date

2017-11-21 00:00:00

pages

2198-2211

issue

8

issn

2211-1247

pii

S2211-1247(17)31579-6

journal_volume

21

pub_type

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