Enhancer cooperativity as a novel mechanism underlying the transcriptional regulation of E-cadherin during mesenchymal to epithelial transition

Alotaibi, Hani; Basilicata, M. Felicia; Shehwana, Huma; Kosowan, Tyler; Schreck, Ilona; Braeutigam, C; Konu, Özlen; Brabletz, Thomas; Stemmler, Marc P.

doi:10.1016/j.bbagrm.2015.01.005

Cited by 42 publications

(79 citation statements)

References 54 publications

(39 reference statements)

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“…Her2 tumors contain the smallest NR2A2 amounts. In mammary-glands, NR2A1 has been the object of few studies [77–81], while no studies on NR2A2 are available. NR2A1 may have oncosuppressive properties [77], as it is down-regulated in mammary epithelial-cells undergoing epithelial-to-mesenchymal transition (EMT).…”

Section: Enigmatic-orphansmentioning

confidence: 99%

Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer

et al. 2016

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Breast-cancer is heterogeneous and consists of various groups with different biological characteristics. Innovative pharmacological approaches accounting for this heterogeneity are needed. The forty eight human Nuclear-Hormone-Receptors are ligand-dependent transcription-factors and are classified into Endocrine-Receptors, Adopted-Orphan-Receptors (Lipid-sensors and Enigmatic-Orphans) and Orphan-receptors. Nuclear-Receptors represent ideal targets for the design/synthesis of pharmacological ligands. We provide an overview of the literature available on the expression and potential role played by Lipid-sensors, Enigmatic-Orphans and Orphan-Receptors in breast-cancer. The data are complemented by an analysis of the expression levels of each selected Nuclear-Receptor in the PAM50 breast-cancer groups, following re-elaboration of the data publicly available. The major aim is to support the idea that some of the Nuclear-Receptors represent largely unexploited therapeutic-targets in breast-cancer treatment/chemo-prevention. On the basis of our analysis, we conclude that the Lipid-Sensors, NR1C3, NR1H2 and NR1H3 are likely to be onco-suppressors in breast-cancer. The Enigmatic-Orphans, NR1F1 NR2A1 and NR3B3 as well as the Orphan-Receptors, NR0B1, NR0B2, NR1D1, NR2F1, NR2F2 and NR4A3 exert a similar action. These Nuclear-Receptors represent candidates for the development of therapeutic strategies aimed at increasing their expression or activating them in tumor cells. The group of Nuclear-Receptors endowed with potential oncogenic properties consists of the Lipid-Sensors, NR1C2 and NR1I2, the Enigmatic-Orphans, NR1F3, NR3B1 and NR5A2, as well as the Orphan-Receptors, NR2E1, NR2E3 and NR6A1. These oncogenic Nuclear-Receptors should be targeted with selective antagonists, reverse-agonists or agents/strategies capable of reducing their expression in breast-cancer cells.

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Section: Enigmatic-orphansmentioning

confidence: 99%

Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer

et al. 2016

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“…human immortalization breast cell line (HMLE) [1,12], mouse inner medullar collecting duct (mIMCD-3) [5], primary keratinocytes or human immortalization keratinocytes (HaCat) [13], and nontumorigenic mouse mammary gland cell line (NmuMG) [14], Grhls may play some roles in regulating mesenchymal-epithelial transition under physiological conditions. Though Alotaibi et al [14] demonstrated that Grhl3 could also activate E-cadherin expression in the hepatoma carcinoma cells derived from mesoderm, it has not been reported the Grhl3 functions during mesoderm development. In fact, Grhl3 can act as an activator or repressor on the target genes [6,21].…”

Section: Discussionmentioning

confidence: 99%

“…E-cadherin, an essential molecule for the formation of adhesion junction, is critical to form the intercellular contacts and frequently downregulated in the later stage of tumorigenesis. Some previous studies indicated that Grainyhead family factors are the activators of E-cadherin in the physiological context [1,5,[12][13][14]. Since Grhl3 also represses the expression of some target genes [6], we hypothesized that Grhl3 may regulate cancer cell migration and invasion by the downregulation of E-cadherin.…”

Section: Introductionmentioning

confidence: 99%

Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin

Zhao¹,

Guo²,

Tu³

et al. 2016

ABBS

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Grainyhead genes are involved in wound healing and developmental neural tube closure. Metastasis is a multistep process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant organs. The adhesion protein E-cadherin plays an essential role in metastasis. In light of the high degree of similarity between the epithelial-mesenchymal transition (EMT) occurring in wound-healing processes and the EMT occurring during the acquisition of invasiveness in skin or breast cancer, we investigated the role of the Grainyhead genes in cancer invasion. Here, we show that there is an inverse relationship between Grainyhead-like 3 (Grhl3) and E-cadherin expression in some epithelial tumor cell lines. Overexpression of Grhl3 in the E-cadherin-positive epithelial tumor cell line, characterized by less invasiveness, generated a transcriptional blockage of the E-cadherin gene and promoted cell migration and cell invasion. Conversely, Grhl3 depletion inhibited cell migration and cell invasion and was associated with a gain of E-cadherin expression. To further explore the mechanism by which Grhl3 regulated E-cadherin expression, an E-cadherin promoter report analysis was performed and results showed that Grhl3 repressed E-cadherin gene expression by directly or indirectly binding to the E-boxes present in the proximal E-cadherin promoter. Taken together, our findings define a major role for Grhl3 in the induction of migration and invasion by the downregulation of E-cadherin in cancer cells.

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“…Mammary gland ducts 17,19,20 Breast cancer [17][18][19][20][21] Colon and rectum 7 Colorectal cancer 23,24 Lining of the stomach 26 Gastric cancer 25,26 Oral epithelium 7 Oral squamous cell carcinoma 27 Liver ducts 45 Hepatocellular carcinoma 28 Renal epithelium 46 Clear cell renal cell carcinoma Skin cancer 32,33 Mammary gland ducts 37 Breast cancer [34][35][36] Lung airways 7 Lung cancer 37,38 Urinary bladder 44 ?…”

Section: Future Perspectivesmentioning

confidence: 99%

“…In contradiction to these findings, in a recent publication it was reported that GRHL3 positively regulates the expression of E-cadherin in lung cancer, which would be suggestive of a tumor suppressive function. 37 However, the authors of the latter report did not specify the subtype of lung cancer studied, so it is still possible that GRHL3 acts as a tumor suppressor in some types of lung cancer and fulfils a different function in other types of lung cancer.…”

mentioning

confidence: 99%

Recent discoveries concerning the involvement of transcription factors from the Grainyhead-like family in cancer

Mlacki

Kikulska

Krzywińska

et al. 2015

Exp Biol Med (Maywood)

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The Grainyhead-like (GRHL) family of transcription factors has three mammalian members, which are currently termed Grainyhead-like 1 (GRHL1), Grainyhead-like 2 (GRHL2), and Grainyhead-like 3 (GRHL3). These factors adopt a DNA-binding immunoglobulin fold homologous to the DNA-binding domain of key tumor suppressor p53. Their patterns of expression are tissue and developmentally specific. Earlier studies of the GRHL proteins focused on their functions in mammalian development. In recent years, these factors have been linked to many different types of cancer: squamous cell carcinoma of the skin, breast cancer, gastric cancer, hepatocellular carcinoma, colorectal cancer, clear cell renal cell carcinoma, neuroblastoma, prostate cancer, and cervical cancer. The roles of GRHL proteins in these various types of cancer are complex, and in some cases appear to be contradictory: they can serve to promote cancer development, or they may act as tumor suppressors, depending on the particular GRHL protein involved and on the cancer type. The reasons for obvious discrepancies in results from different studies remain unclear. At the molecular level, the GRHL transcription factors regulate the expression of genes whose products are involved in cellular proliferation, differentiation, adhesion, and polarity. We herein review the roles of GRHL proteins in cancer development, and we critically examine relevant molecular mechanisms, which were proposed by different authors. We also discuss the significance of recent discoveries implicating the involvement of GRHL transcription factors in cancer and highlight potential future applications of this knowledge in cancer treatment.

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Enhancer cooperativity as a novel mechanism underlying the transcriptional regulation of E-cadherin during mesenchymal to epithelial transition

Cited by 42 publications

References 54 publications

Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer

Lipid-sensors, enigmatic-orphan and orphan nuclear receptors as therapeutic targets in breast-cancer

Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin

Recent discoveries concerning the involvement of transcription factors from the Grainyhead-like family in cancer

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