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

Abstract

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.

Grainyhead-like 2 Reverses the Metabolic Changes Induced by the Oncogenic Epithelial–Mesenchymal Transition: Effects on Anoikis

“…Previously, we reported that GRHL2 suppresses the oncogenic EMT, i.e., promotes MET (15–17). The loss of GRHL2 expression is associated with aggressive, metastatic breast tumor types that contain an unusually large fraction of EMT-like subpopulations, and in the cancer stem cell-like subpopulation of tumors resulting from EMT and/or drug resistance.…”

Grainyhead-like 2 downstream targets act to suppress EMT during neural tube closure

“…The Claudin-low subtype of breast cancer expresses low levels of GRHL2, E-cadherin and claudin 4, is highly metastatic, and GRHL2 expression positively correlates with distant metastasis-free survival (Cieply et al, 2012(Cieply et al, , 2013Mlacki et al, 2015). GRHL2 acts as a suppressor of EMT in breast cancer cell lines and can directly repress the EMT-promoting TF ZEB1 (Cieply et al, 2012(Cieply et al, , 2013.…”

Stable Binding of the Conserved Transcription Factor Grainy Head to its Target Genes ThroughoutDrosophila melanogasterDevelopment

“…Similar processes have been implicated in cancer metastasis, where transformed cells spread from a primary tumor in an EMT-like process, and relocate to additional sites in the body by reverting back to a mesenchymal cell fate (Kalluri and Weinberg 2009;Thiery et al 2009). Misexpression of each of the mammalian Grh-family members has been associated with a range of epithelium-derived cancers (Mlacki et al 2015). Given the function of Grh-family members in driving epithelial cell fate, it was predicted that these proteins might function as tumor suppressors by suppressing the EMT and metastasis.…”