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Deregulated GATA6 modulates stem cell‐like properties and metabolic phenotype in hepatocellular carcinoma
Author(s) -
Tan HanWei,
Leung Carmen OiNing,
Chan Kristy KwanShuen,
Ho Daniel WaiHung,
Leung MingSum,
Wong ChunMing,
Ng Irene OiLin,
Lo Regina CheukLam
Publication year - 2019
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.32248
Subject(s) - gata6 , biology , cancer research , gene knockdown , carcinogenesis , epithelial–mesenchymal transition , reprogramming , stem cell , transcription factor , hepatocyte nuclear factors , metastasis , cell , microbiology and biotechnology , cell culture , cancer , genetics , gene
Accumulating evidence illustrates the significance of cell plasticity in the molecular biology of liver cancer. Reprogramming of mature parenchymal cells to a less differentiated state by key molecular targets contributes to the pathogenesis of hepatocellular carcinoma (HCC). Hereby, we investigated the role of GATA6, a transcription factor implicated in hepatocyte lineage specification, in HCC. Our results demonstrated a lower expression of GATA6 in HCC tissues compared to the corresponding nontumoral liver tissues. Moreover, GATA6 underexpression, as observed in about 50% cases in our clinical cohort, was associated with a poorer degree of tumor cell differentiation and worse disease‐free survival outcome. In vitro, silencing of GATA6 in HCC cells augmented cell migration and invasion abilities of HCC cells by activating epithelial–mesenchymal transition. Self‐renewal was also enhanced in vitro . Consistently, in vivo tumorigenicity and self‐renewal was promoted upon GATA6 knockdown. Notably, suppression of GATA6 converts HCC cells to a metabolic phenotype recapitulating stem‐cell state. Expression of glycolytic markers was elevated in GATA6‐knockdown clones accompanied by increased glucose uptake; while overexpression of GATA6 resulted in opposite effects. Further to this, we identified that GATA6 bound to the promoter region of PKM gene and regulated PKM2 transcription. Taken together, downregulation of GATA6 directs HCC cells to glycolytic metabolism and fosters tumorigenicity, self‐renewal and metastasis. GATA6 is a transcriptional regulator and a genetic switch that converts the phenotypic reprogramming of HCC cells. It is a potential prognostic biomarker and therapeutic target for liver cancer.