Grainyhead-like 2 inhibits the coactivator p300, suppressing tubulogenesis and the epithelial–mesenchymal transition

Abstract

GRHL2 suppresses EMT to give a default epithelial phenotype. GRHL2 inhibits this process through the histone acetyltransferase coactivator p300, repressing the partial EMT and preventing induction of MMPs. The results demonstrate novel roles for p300 and GRHL2 in promoting or suppressing EMT in morphogenesis and tumor progression.

Network analysis of ChIP-seq data by VULCAN identifies GRHL2 as a key co-regulator of ERa in luminal breast cancer

“…These results are consistent with previous findings that GRHL2 inhibits P300 [44] and, while the ER complex results in the activation of eRNA transcription at these sites, that GRHL2 plays a role in finetuning or modulating this process.…”

“…Similar results were observed with the MDAMB231 model, where expression of GRHL2 resulted in reversal of EMT [30] . This result has been recapitulated in hepatocytes, where GRHL2 was found to suppress EMT by inhibiting P300 [44] . The ability to suppress EMT has also been noted in prostate cancer, another cancer driven by a steroid hormone receptor (AR), and the genes regulated by GRHL2 are linked to disease progression [46] .…”

“…A conserved alphahelix between residues 425437 of GRHL2 has previously been shown to inhibit P300 [44] . We therefore overexpressed GRHL2 Δ425437, a previously demonstrated nonp300inhibitory mutant [44], [45] , in three ER positive breast cancer cell lines (MCF7, T47D…”

Transcriptional mechanisms coordinating tight junction assembly during epithelial differentiation

“…However, it is unclear whether GRHL2 is directly involved in the repression of the Smad signaling pathway in differentiating cells. More recently, studies performed in the context of tubulogenesis and tumor progression supported a mechanism whereby GRHL2 enforces an epithelial phenotype by inhibiting the HAT activity of the coactivator p300 via direct physical interaction . As a coactivator, p300 interacts with several DNA‐binding factors to promote the activation of a mesenchymal differentiation program and facilitate the regulation of several genes encoding mesenchymal‐associated proteins, such as matrix metalloproteinases .…”

“…More recently, studies performed in the context of tubulogenesis and tumor progression supported a mechanism whereby GRHL2 enforces an epithelial phenotype by inhibiting the HAT activity of the coactivator p300 via direct physical interaction. 71 As a coactivator, p300 interacts with several DNAbinding factors to promote the activation of a mesenchymal differentiation program and facilitate the regulation of several genes encoding mesenchymal-associated proteins, such as matrix metalloproteinases. 72,73 Thus, the functional inhibition of p300 by GRHL2 suggests a mechanism whereby GRHL2 ensures epithelial differentiation via complete repression of an EMT program.…”