Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 127, Issue 9, Pages 3527-3542Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI93488
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Funding
- National Medical Research Council (NMRC) [MOHIAFCAT2/001/2014]
- Biomedical Research Council (BMRC) [EDB-IAF311020]
- National Cancer Centre Research Fund (NCCRF) pilot grant
- Terry Fox Foundation
- National Cancer Centre Singapore
- case GI SPORE [P50CA150964]
- Comprehensive Cancer Center grant [P30 CA043703]
- Cleveland Clinic HCC Center of Excellence grants
- NIH [RO1 CA204373]
- Grants-in-Aid for Scientific Research [16H05338] Funding Source: KAKEN
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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 ouf GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sstain replicative precursor phenotype.
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