Roles of Grainyhead-like transcription factors in cancer

Frisch, Steven M.; Farris, Joshua C.; Pifer, Phillip M.

doi:10.1038/onc.2017.178

Cited by 65 publications

(63 citation statements)

References 126 publications

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“…GRHL2 can inhibit and reverse EMT and associated molecular and/or morphological traits. Specifically, overexpression of GRHL2 has been shown to induce epithelial gene expression, inhibit mesenchymal gene expression, restore metabolic reprogramming caused by EMT, and suppress tumor cell migration/invasion, at least in breast and ovarian cancer cell lines [46]. It can also activate directly or indirectly other drivers of an epithelial phenotype such as p63 [57,58], OVOL2 [59,60], and miR-200 [38,61].…”

Section: Discussionmentioning

confidence: 99%

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

Jia

Tripathi

Chakraborty

et al. 2020

Preprint

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Epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET) are central to metastatic aggressiveness and therapy resistance in solid tumors. While molecular determinants of both processes have been extensively characterized, the heterogeneity in the response of tumor cells to EMT and MET inducers has come into focus recently, and has been implicated in the failure of anti-cancer therapies. Recent experimental studies have shown that some cells can undergo an irreversible EMT depending on the duration of exposure to EMT-inducing signals. While the irreversibility of MET, or equivalently, resistance to EMT, has not been studied in as much detail, evidence supporting such behavior is slowly emerging. Here, we identify two possible mechanisms that can underlie resistance of cells to undergo EMT: epigenetic feedback in ZEB1/GRHL2 feedback loop and stochastic partitioning of biomolecules during cell division. Identifying the ZEB1/GRHL2 axis as a key determinant of epithelial-mesenchymal plasticity across many cancer types, we use mechanistic mathematical models to show how GRHL2 can be involved in both the abovementioned processes, thus driving an irreversible MET. Our study highlights how an isogenic population may contain subpopulation with varying degrees of susceptibility or resistance to EMT, and proposes a next set of questions for detailed experimental studies characterizing the irreversibility of MET/resistance to EMT.

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Section: Discussionmentioning

confidence: 99%

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

Jia

Tripathi

Chakraborty

et al. 2020

Preprint

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“…The GRH gene was discovered in Drosophila and its mammalian homologs have three members (GRHL1, GRHL2 and GRHL3) [5].…”

Section: Introductionmentioning

confidence: 99%

“…GRH deficiency leads to failure of complete neural tube closure, epidermal barrier formation, trachea elongation and epidermal wound response [5][6][7]. GRHL2 is one of three mammalian homologues of the GRH gene, which has been investigated in cancer development.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide identification of binding sites of GRHL2 in luminal-like and basal A subtypes of breast cancer

Danen

et al. 2020

Preprint

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Grainyhead like 2 (GRHL2) is one of three mammalian homologues of the grainyhead (GRH) gene. It suppresses the oncogenic epithelialmesenchymal transition (EMT), acting as a tumor suppressor. On the other hand, GHRL2 promotes cell proliferation by increasing human telomerase reverse transcriptase (hTERT) activity, serving as a tumor promoter. According to gene expression profiling, breast cancer can be divided into basal-like (basal A and basal B), luminal-like, HER2 enriched, claudin-low and normal-like subtypes. To identify common and subtype-specific genomic binding sites of GRHL2 in breast cancer, GRHL2 ChIP-seq was performed in three luminal-like and three basal A human breast cancer cell lines. Most binding sites of GRHL2 were found in intergenic and intron regions. 13,351 common binding sites were identified in basal A cells, which included 551 binding sites in gene promoter regions. For luminal-like cells, 6,527 common binding sites were identified, of which 208 binding sites were found in gene promoter regions. Basal A and luminal-like breast cancer cells shared 4711 GRHL2 binding sites, of which 171 binding sites were found in gene promoter regions. The identified GRHL2-binding motifs are all identical to a motif reported for human ovarian cancer, indicating conserved GRHL2 DNA-binding among human cancer cells. Notably, no binding sites of GRHL2 were detected in the promoter regions of several established EMT-related genes, including CDH1, ZEB1, ZEB2 and CDH2 genes. Collectively, this study provides a comprehensive overview of interactions of GRHL2 with DNA and lays the foundation 3 for further understanding of common and subtype-specific signaling pathways regulated by GRHL2 in breast cancer.

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“…For example, the cadherin-switch, a well-described feature of EMT, involves the repression of cadherin 1 ( CDH1 ; E-cadherin) and activation of cadherin 2 ( CDH2 ; N-cadherin) gene expression, with the reverse being observed in MET. In addition, an inverse correlation is observed between the mesenchymal-associated transcription factor ZEB1 and two epithelial-associated transcription factors, ovo-like 2 (OVOL2) and grainy head-like transcription factor 2 (GRHL2), known to directly repress ZEB1 transcription [6, 8–10].…”

Section: Introductionmentioning

confidence: 99%

ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing

Frausto

Chung

Boere

et al. 2019

Preprint

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AJA) 34 ZEB1 and corneal endothelial cell biology 2 ABSTRACT 35The zinc finger e-box binding homeobox 1 (ZEB1) transcription factor is a master regulator of 36 the epithelial to mesenchymal transition (EMT), and of the reverse mesenchymal to epithelial 37 transition (MET) processes. ZEB1 plays an integral role in mediating cell state transitions during 38 cell lineage specification, wound healing and disease. EMT/MET are characterized by distinct 39 changes in molecular and cellular phenotype that are generally context-independent. Posterior 40 polymorphous corneal dystrophy (PPCD), associated with ZEB1 insufficiency, provides a new 41 biological context in which to understand and evaluate the classic EMT/MET paradigm. PPCD is 42 characterized by a cadherin-switch and transition to an epithelial-like transcriptomic and cellular 43 phenotype, which we study in a cell-based model of PPCD generated using CRISPR-Cas9-44 mediated ZEB1 knockout in corneal endothelial cells (CEnCs). Transcriptomic and functional 45 studies support the hypothesis that CEnC undergo a MET-like transition in PPCD, termed 46 endothelial to epithelial transition (EnET), and lead to the conclusion that EnET may be 47 (EMT) or the reverse process, mesenchymal to epithelial (MET). EMT is characterized by 54 distinct molecular and morphologic changes in which epithelial cells lose an epithelial-associated 55 gene expression profile, apicobasal polarity and intercellular adhesions, and gain a mesenchymal-56 associated gene expression profile and increased migratory capacity. Conversely, the reverse of 57 the EMT process effectively characterizes MET. EMT and MET are tightly regulated CST 58 processes involving the regulation of many genes in a cell-type-independent manner, and for 59 which stable transition states have been identified [2][3][4][5][6][7]. For example, the cadherin-switch, a well-60 described feature of EMT, involves the repression of cadherin 1 (CDH1; E-cadherin) and 61 activation of cadherin 2 (CDH2; N-cadherin) gene expression, with the reverse being observed in 62MET. In addition, an inverse correlation is observed between the mesenchymal-associated 63 transcription factor ZEB1 and two epithelial-associated transcription factors, ovo-like 2 (OVOL2) 64 and grainy head-like transcription factor 2 (GRHL2), known to directly repress ZEB1 65 transcription [6,[8][9][10]. 66The corneal endothelium is present on the internal surface of the cornea, which is 67 comprised of three cell types: the external corneal epithelium, the central connective tissue 68 containing a "resting" fibroblast-like cell type (i.e., keratocytes), and the corneal endothelium. 69The corneal endothelium demonstrates an epithelial organization (i.e., simple squamous 70 epithelium), and expresses both epithelial-and mesenchymal-associated genes [11]. Nevertheless, 71 corneal endothelial cells (CEnC) are considered distinct from most epithelial cell types due to 72 their embryonic origin, unique function and gene expression profile [11]. Therefore, based on 73 anato...

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Roles of Grainyhead-like transcription factors in cancer

Cited by 65 publications

References 126 publications

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

Epigenetic feedback and stochastic partitioning during cell division can drive resistance to EMT

Genome-wide identification of binding sites of GRHL2 in luminal-like and basal A subtypes of breast cancer

ZEB1 insufficiency causes corneal endothelial cell state transition and altered cellular processing

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