Suppression of the Epithelial–Mesenchymal Transition by Grainyhead-like-2

Abstract

Grainyhead genes are involved in wound healing and developmental neural tube closure. In light of the high degree of similarity between the epithelial-mesenchymal transitions (EMT) occurring in wound healing processes and the cancer stem cell-like compartment of tumors, including TGF-β-dependence, we investigated the role of the Grainyhead gene, Grainyhead-Like-2 (GRHL2) in oncogenic EMT. GRHL2 was down-regulated specifically in the claudin-low subclass breast tumors and in basal-B subclass breast cancer cell lines. GRHL2 suppressed TGF-β-induced, Twist-induced or spontaneous EMT, enhanced anoikis-sensitivity, and suppressed mammosphere generation in mammary epithelial cells. These effects were mediated in part by suppression of ZEB1 expression via direct repression of the ZEB1 promoter. GRHL2 also inhibited Smad-mediated transcription and it upregulated mir200b/c as well as the TGF-β receptor antagonist, BMP2. Lastly, ectopic expression of GRHL2 in MDA-MB-231 breast cancer cells triggered a mesenchymal-to-epithelial transition and restored sensitivity to anoikis. Taken together, our findings define a major role for GRHL2 in the suppression of oncogenic EMT in breast cancer cells.

Downregulation of GRHL2 inhibits the proliferation of colorectal cancer cells by targeting ZEB1

“…GRHL2 plays an important role in epidermal junctions, in part due to its activation of target genes including E-cadherin, 14 by binding to a cis-regulatory region localized in intron 2 of the E-cadherin gene.…”

“…12 In the context of cancer, GRHL2 has been reported to function as a tumor suppressor. 13,14 However, increasing evidence indicates that GRHL2 may have an oncogenic role in cancer development. [15][16][17][18] These controversial results suggest that the role of GRHL2 is possibly tumor-specific and highly dependent on its targets in different cancer cells.…”

“…19 Mutual regulatory relationships have been defined for GRHL2 and ZEB1, 14,19 and a functional and reciprocal relationship between ZEB1 and GRHL2 has been established. 40 In our study, we demonstrated that ZEB1 was a downstream target of GRHL2 in the regulation of CRC cell proliferation.…”

Suppression of Early Hematogenous Dissemination of Human Breast Cancer Cells to Bone Marrow by Retinoic Acid–Induced 2

“…4A ). shRNA-mediated knockdown of RAI2 protein expression caused downregulation of ERα protein expression in all three of the tested cell lines and a concomitant downregulation of the expression of GATA3, FOXA1, and GRHL2 proteins, which are known to be key regulators of breast epithelial differentiation (14)(15)(16). Furthermore, Western blot analysis further revealed decreased protein expression of the transcriptional coregulators carboxyl-terminal binding proteins (CtBP) 1 and 2 ( Furthermore, loss of RAI2 protein expression led to an apparent alteration in cellular morphology.…”

A Grainyhead-Like 2/Ovo-Like 2 Pathway Regulates Renal Epithelial Barrier Function and Lumen Expansion

“…[8][9][10] Grhl2 was reported to participate in epithelial morphogenesis and differentiation in cultured airway, 11 in biliary and hepatic epithelia, 12,13 and in tumorigenesis of skin and mammary epithelial cells. 14,15 However, the underlying genetic networks are incompletely understood.…”