GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition
Francis O. Enane, … , Han Chong Toh, Yogen Saunthararajah
Francis O. Enane, … , Han Chong Toh, Yogen Saunthararajah
Published July 31, 2017
Citation Information: J Clin Invest. 2017;127(9):3527-3542. https://doi.org/10.1172/JCI93488.
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Research Article Genetics Oncology

GATA4 loss of function in liver cancer impedes precursor to hepatocyte transition

Abstract

The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation. HCC mimicked this gene expression profile, even in cases that were morphologically classified as well differentiated. HCC with intact chromosome 8p also featured GATA4 loss of function via GATA4 germline mutations that abrogated GATA4 interactions with a coactivator, MED12, or by inactivating mutations directly in GATA4 coactivators, including ARID1A. GATA4 reintroduction into GATA4-haploinsufficient HCC cells or ARID1A reintroduction into ARID1A-mutant/GATA4-intact HCC cells activated hundreds of hepatocyte genes and quenched the proliferative precursor program. Thus, disruption of GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sustain replicative precursor phenotype.

Authors

Francis O. Enane, Wai Ho Shuen, Xiaorong Gu, Ebrahem Quteba, Bartlomiej Przychodzen, Hideki Makishima, Juraj Bodo, Joanna Ng, Chit Lai Chee, Rebecca Ba, Lip Seng Koh, Janice Lim, Rachael Cheong, Marissa Teo, Zhenbo Hu, Kwok Peng Ng, Jaroslaw Maciejewski, Tomas Radivoyevitch, Alexander Chung, London Lucien Ooi, Yu Meng Tan, Peng-Chung Cheow, Pierce Chow, Chung Yip Chan, Kiat Hon Lim, Lisa Yerian, Eric Hsi, Han Chong Toh, Yogen Saunthararajah

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Figure 6

Atypical HCC containing a rare germline GATA4 mutation.

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Atypical HCC containing a rare germline GATA4 mutation. (A) GATA4 germli...
(A) GATA4 germline missense mutation (V267M) found in 2 of 51 patients (4%). Sanger and targeted deep sequencing of HCC, adjacent nonmalignant liver, and peripheral blood mononuclear cells (Supplemental Figure 7). (B) Frequency of this mutation in healthy individual populations from Singapore (Sing.) and China (34–36) ***P < 0.001, Fisher’s exact test. (C) HCC cases with GATA4 mutation had near-normal karyotype. Karyotype analyzed by SNP array and imaged by IGV. Pathstage, American Joint Committee on Cancer staging system. HepBsAg, hepatitis B surface antigen; Del, GATA4 locus deletion.