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

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

doi:10.1172/jci93488

Cited by 40 publications

(38 citation statements)

References 80 publications

(94 reference statements)

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“…The complex balance between cell proliferation and differentiation drives commitment into a lineage while ending cell proliferation. Thus, impeded lineage differentiation may result in cell proliferation and cancer, and these changes are reflected in the morphology and architecture of cells [77,78]. The degree of differentiation in a tumor is used to distinguish malignant from benign tumors, and it is a central aspect of the histopathological classification of solid tumors [79].…”

Section: During Differentiationmentioning

confidence: 99%

Non-Canonical Functions of the Gamma-Tubulin Meshwork in the Regulation of the Nuclear Architecture

Corvaisier

Alvarado-Kristensson

2020

Cancers

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The nuclear architecture describes the organization of the various compartments in the nucleus of eukaryotic cells, where a plethora of processes such as nucleocytoplasmic transport, gene expression, and assembly of ribosomal subunits occur in a dynamic manner. During the different phases of the cell cycle, in post-mitotic cells and after oncogenic transformation, rearrangements of the nuclear architecture take place, and, among other things, these alterations result in reorganization of the chromatin and changes in gene expression. A member of the tubulin family, γtubulin, was first identified as part of a multiprotein complex that allows nucleation of microtubules. However, more than a decade ago, γtubulin was also characterized as a nuclear protein that modulates several crucial processes that affect the architecture of the nucleus. This review presents the latest knowledge regarding changes that arise in the nuclear architecture of healthy cells and under pathological conditions and, more specifically, considers the particular involvement of γtubulin in the modulation of the biology of the nuclear compartment.

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Section: During Differentiationmentioning

confidence: 99%

Non-Canonical Functions of the Gamma-Tubulin Meshwork in the Regulation of the Nuclear Architecture

Corvaisier

Alvarado-Kristensson

2020

Cancers

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“…S7). Besides, while loss of function of GATA4 via germline mutation was recently reported in HCC, 38 its expression was apparently independent of GATA6 from correlation analysis from the database (Supporting Information Fig. S7).…”

Section: Discussionmentioning

confidence: 71%

Deregulated GATA6 modulates stem cell‐like properties and metabolic phenotype in hepatocellular carcinoma

Tan

Leung

Chan

et al. 2019

Intl Journal of Cancer

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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.

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“…The complex balance between cell proliferation and differentiation drives commitment into a lineage while ending cell proliferation. Thus, impeded lineage differentiation may result in cell proliferation and cancer, and these changes are reflected in the morphology and architecture of cells [78,79]. The degree of differentiation in a tumour is used to distinguish malignant from benign tumours, and it is a central aspect in the histopathological classification of solid tumours [80].…”

Section: During Differentiationmentioning

confidence: 99%

Non-Canonical Functions of the γTubulin Meshwork in the Regulation of the Nuclear Architecture

Corvaisier¹,

Alvarado-Kristensson²

2020

Preprint

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The nuclear architecture describes the organization of the various compartments in the nucleus of eukaryotic cells, where a plethora of processes such as nucleocytoplasmic transport, gene expression, and assembly of ribosomal subunits occur in a dynamic manner. During the different phases of the cell cycle, in post-mitotic cells and after oncogenic transformation, rearrangements of the nuclear architecture take place, and, among other things, these alterations result in reorganization of the chromatin and changes in gene expression. A member of the tubulin family, tubulin, was first identified as part of a multiprotein complex that allows nucleation of microtubules. However, more than a decade ago, γ tubulin was also characterized as a nuclear protein that modulates several crucial processes that affect the architecture of the nucleus. This review presents the latest knowledge regarding changes that arise in the nuclear architecture of healthy cells and under pathological conditions and, more specifically, considers the particular involvement of tubulin in the modulation of the biology of the nuclear compartment.

show abstract

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

Cited by 40 publications

References 80 publications

Non-Canonical Functions of the Gamma-Tubulin Meshwork in the Regulation of the Nuclear Architecture

Non-Canonical Functions of the Gamma-Tubulin Meshwork in the Regulation of the Nuclear Architecture

Deregulated GATA6 modulates stem cell‐like properties and metabolic phenotype in hepatocellular carcinoma

Non-Canonical Functions of the γTubulin Meshwork in the Regulation of the Nuclear Architecture

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