Grainyhead-like Protein 2: The Emerging Role in Hormone-Dependent Cancers and Epigenetics

Reese, Rebecca; Harrison, Melissa M.; Alarid, Elaine T.

doi:10.1210/en.2019-00213

Cited by 19 publications

(19 citation statements)

References 109 publications

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“…30 Finally, GRHL2 acts as an oncogene in some subtypes of breast cancer, which was extensively discussed in a recent review. 4…”

Section: Grainyhead-like Factors Acting As Oncogenesmentioning

confidence: 99%

“…These discrepancies were extensively discussed in recent reviews. 1,3,4 A question mark indicates that no tumor promoting roles have ever been reported for GRHL1.…”

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

“…Many review articles have recently been published on this topic. 1–4 These articles discuss many of the important aspects of GRHL involvement in cancer. For this reason, we decided to focus our review on those GRHL characteristics that do not receive enough attention, yet in our opinion are very important.…”

Section: Introductionmentioning

confidence: 99%

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Grainyhead-like transcription factors in cancer – Focus on recent developments

Kotarba

Taracha-Wisniewska

Wilanowski

2020

Exp Biol Med (Maywood)

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The role of grainyhead-like transcription factors in cancer has been widely investigated by the scientific community. However, some of its aspects do not seem to be adequately appreciated, and these are the topic of our article. In addition to their well-documented role as tumor suppressors, in many cases the grainyhead-like proteins perform tumor-promoting functions, which make them potential drug targets. However, it is difficult to directly target transcription factors, which is why we recommend an alternative approach. The transcriptional transactivation activity of grainyhead-like transcription factors is regulated by phosphorylation, and protein kinases are much more feasible drug targets. Studying the phosphorylation of grainyhead-like proteins may thus allow to identify protein kinases regulating the activity of these factors, and design inhibitors of these kinases to indirectly regulate the activity of grainyhead-like transcription factors. There are many somatic mutations in the GRHL genes that occur during cancer development. These mutations are widely distributed across the GRHL loci, and these mutations are very rare. For this reason, they are unlikely to become targets of future therapies, nevertheless some of them may be driver mutations and studying them may provide important novel information about the regulation of functioning of the GRHL genes and proteins. Analogous information may be obtained by studying single nucleotide polymorphisms in GRHL genes that are associated with disease risk. Such polymorphisms may also prove useful in identifying individuals with an increased risk of a particular disease. Impact statement In the present article, we focus on relatively little appreciated aspects of involvement of the grainyhead-like (GRHL) transcription factors in cancer. These aspects are nevertheless very important for the functioning of GRHL proteins, as well as for cancer development. Some of the GRHL factors perform tumor-promoting functions in certain types of cancer, which makes them potential drug targets. Much information is available about somatic cancer mutations in the GRHL genes, yet there are very few analyses of these mutations in the scientific literature. The activity of GRHL transcription factors is controlled by phosphorylation, and we suggest that regulating their phosphorylation with specific protein kinases provides an alternative approach to modify the activity of GRHL proteins. Some single nucleotide polymorphisms (SNPs) in the GRHL genes are associated with disease risk. Studying such SNPs may yield new information about the functioning of GRHL genes and proteins, and may also allow to identify people with an increased risk of a particular disease.

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“…30 Finally, GRHL2 acts as an oncogene in some subtypes of breast cancer, which was extensively discussed in a recent review. 4…”

Section: Grainyhead-like Factors Acting As Oncogenesmentioning

confidence: 99%

“…These discrepancies were extensively discussed in recent reviews. 1,3,4 A question mark indicates that no tumor promoting roles have ever been reported for GRHL1.…”

Section: Post-translational Modifications Of Grainyhead-like Proteinsmentioning

confidence: 99%

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Grainyhead-like transcription factors in cancer – Focus on recent developments

Kotarba

Taracha-Wisniewska

Wilanowski

2020

Exp Biol Med (Maywood)

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“…Grainyhead-like 2 (GRHL2) is considered an epithelial master transcription factor. Acting as a pioneer transcription factor, GRHL2 localizes to genomic loci and binds closed chromatin regions, subsequently recruiting chromatin remodeling enzymes in order to alter histone modifications, thereby loosening repressive chromatin and providing topography permissive for transcription factor binding (Jacobs et al, 2018;Reese, Harrison, & Alarid, 2019). Many canonical epithelial genes contain GRHL2 binding sites in their regulatory regions including CDH1, ELF3, OVOL2, RAB25, p63, CLDN4 (Frisch, Farris, & Pifer, 2017) .…”

Section: ………………………………………………Materials and Methods 94………………………………………mentioning

confidence: 99%

“…In addition to its integral role in specific tissue and organ development, GRHL2 modulation has implications in cancer. The specific roles of Grainyhead-like proteins in cancer have been reviewed extensively (Frisch et al, 2017;He et al, 2020;Kotarba, Taracha-Wisniewska, & Wilanowski, 2020;Reese et al, 2019). Low GRHL2 expression, according to IHC, in a subset of breast cancer cells correlates with worse prognosis and lymph node metastasis, however, GRHL2 can also increase proliferation in breast cancer cell lines (Werner et al, 2013).…”

Section: ………………………………………………Materials and Methods 94………………………………………mentioning

confidence: 99%

Grainyhead-like 2 Sensitizes Cells to Natural Killer Cell Cytotoxicity and Promotes the Interferon Response

MacFawn¹

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Our research determined that the epithelial master transcription factor Grainyhead-like 2 (GRHL2) promotes sensitivity to Natural Killer (NK) cell-mediated killing, and modulates the interferon I (IFN-I) response of epithelial cells. Immune surveillance by NK cells constitutes a major selective pressure for circulating tumor cells. Epithelial (GRHL2-expressing) cells exhibited significantly higher rates of NK conjugation, a crucial step in direct cell-mediated cytotoxicity. Mechanistically, GRHL2 upregulates expression of intercellular adhesion molecule 1 (ICAM-1), a cell surface molecule critical for NK to target cell synaptogenesis. GRHL2 epigenetically regulates gene expression, and we found that GRHL2 mutant proteins unable to interact with the epigenetic modifiers p300 or KMT2C/D exhibited altered NK sensitivity, and ICAM-1 expression was lost. In summary, the epithelial state, enforced by GRHL2, kept these cells susceptible to NK-mediated cytolysis. Further, our data suggest GRHL2 critically promotes IFN I production in response to a double strand RNA mimetic. The results from these experiments identify novel roles for GRHL2 in maintaining the relationship between epithelial cells and the innate and adaptive arms of the immune system. Chapter I: GRHL2 sensitizes cell to Natural Killer cell cytotoxicity through epigenetic mechanisms. Chapter I: Introduction Perturbation of genetic homeostasis in epithelial cells is a significant driver of tumorigenesis; over 90% of cancers are classified as "carcinoma", which arise from epithelial origin. Epithelial cells are one of many final products of a long and tightly regulated process of differentiation that begins in embryonic stem cells during early mammalian development. In order to limit the self-renewing, pluripotent characteristics of embryonic stem cells, master transcription factors must be turned on, or off, in a concerted manner in order to gradually narrow the potential lineage-specific gene expression programs of different subsets of the rapidly proliferating embryo. Thus, the "terminally" differentiated epithelial cell which comprises various tissue across the body is locked into its identity by the concerted influence of epithelial master transcription factors which promote the expression of epithelial genes (A. F. Chen et al., 2018; Soares & Zhou, 2018), and antagonize the expression and activity of various stemness or mesenchymal master transcription factors. A great body of scientific literature has illustrated the oncogenic characteristics that arise from imbalance of epithelial-mesenchymal transcriptional control (Nieto, Huang, Jackson, & Thiery, 2016; Ribatti, Tamma, & Annese, 2020). These include resistance to chemotherapeutics, increased invasion and motility, anoikisresistance, phenotypic plasticity, aberrant immune response, metabolic reprogramming, and more. Hence, promoting the epithelial "default" state discourages some types of oncogenic progression and represents a lynchpin for understanding tumor biology (Frisch, 1997).

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Estrogen receptor α K303R mutation reorganizes its binding to forkhead box protein A1 regions and induces chromatin opening

et al. 2022

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Background Estrogen receptor alpha (ERα) is a frequently mutated gene in breast cancer (BC). While many studies have investigated molecular dysregulation by hotspot mutations at Y537 and D538, which exhibit an estrogen-independent constitutively active phenotype, the functional abnormalities of other mutations remain obscure. The K303R mutation in primary invasive BC has been implicated with endocrine resistance, tumor size, and lymph node positivity. However, the impact of the K303R mutation on the cell epigenome is yet unknown. Methods and results We introduced the K303R ERα mutant in ERα-negative MDA-MB-453 cells to monitor ERα-dependent transactivation and to perform epigenomic analyses. ATAC-seq and ChIP-Seq analyses indicated that both wild-type (WT) and the K303R mutant associated with Forkhead box (Fox) protein family motif regions at similar rates, even without an ERα-binding sequence, but only the K303R mutant induced chromatin opening at those regions. Biochemical analyses demonstrated that the WT and the K303R mutant can be tethered on DNA by FoxA1 indirectly, but only the K303R/FoxA1/DNA complex can induce associations with the nuclear receptor cofactor 2 (NCOA2). Conclusions These findings suggest that the K303R mutant induces chromatin opening at the Fox binding region through the FoxA1-dependent associations of the K303R mutant to NCOA2 and then probably disrupts the regulation of Fox-target genes, resulting in K303R-related BC events.

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Grainyhead-like Protein 2: The Emerging Role in Hormone-Dependent Cancers and Epigenetics

Cited by 19 publications

References 109 publications

Grainyhead-like transcription factors in cancer – Focus on recent developments

Grainyhead-like transcription factors in cancer – Focus on recent developments

Grainyhead-like 2 Sensitizes Cells to Natural Killer Cell Cytotoxicity and Promotes the Interferon Response

Estrogen receptor α K303R mutation reorganizes its binding to forkhead box protein A1 regions and induces chromatin opening

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