Function of GCN5 in the TGF‑β1‑induced epithelial‑to‑mesenchymal transition in breast cancer

Abstract

Histone acetyltransferase GCN5 is a critical component of the TGF-β/Smad signaling pathway in breast cancer cells; however, it remains unknown whether it is involved in the development and progression of breast cancer. The present study investigated the role of GCN5 in the induction of the EMT by TGF-β1 in breast cancer cells and its underlying molecular mechanism of action. GCN5 activity was elevated and GCN5 mRNA expression and protein expression were increased in MDA-MB231 cells following stimulation with TGF-β1. Furthermore, TGF-β1 stimulation decreased expression of the epithelial cell marker E-cadherin and increased expression of the mesenchymal cell markers, N-cadherin and vimentin, as well as the expression of other EMT markers, including snail and slug. However, these changes were reversed following GCN5 knockdown leading to the downregulation of GCN5 expression. GCN5 knockdown also inhibited the viability, migration and invasion of MDA-MB231 cells, decreased the expression of p-STAT3, p-AKT, MMP9 and E2F1, and increased the expression of p21 in MDA-MB231 cells compared with cells stimulated with TGF-β1 alone. Therefore, GCN5 may work downstream of TGF-β/Smad signaling pathway to regulate the EMT in breast cancer.

Role of JAK/STAT3 Signaling in the Regulation of Metastasis, the Transition of Cancer Stem Cells, and Chemoresistance of Cancer by Epithelial–Mesenchymal Transition

“…Induction of stem cell factor (SCF)/c-KIT signaling by binding of SMAD2 to its promoter activates STAT3, which, in turn, induces TGF-β1 expression by binding to STB-2 region of TGF-β1 promoter via a positive feedback loop [133]. Moreover, TGF-β-induced histone acetyltransferase (GCN5) enhances EMT by activation of STAT3 and AKT and induces the transcriptional activity of TGF-β1 by interacting with R-Smads [134,135]. Intracellular signaling components such as receptors, non-receptor kinases, and other proteins instigate cancer-specific pleiotropic responses through JAK/STAT-mediated transcriptional regulation in cancer progression and aggressiveness.…”

Role of STAT3 signaling pathway in breast cancer

“…ARHGAP24, a Rac-specific Rho GTPase-activating protein (Rho GAP), is found to promote phosphorylation of STAT3 and to increase the expression of MMP2 and MMP9 in breast cancer cells [60]. GCN5, a histone acetyltransferase, is found to upregulate the expression of p-STAT3, p-AKT, MMP9 and E2F1 and promote breast cancer migration and invasion [61].…”

MicroRNA‑1297 downregulation inhibits breast cancer cell epithelial‑mesenchymal transition and proliferation in a FA2H‑dependent manner

“…During the early stages of cancer metastasis, separation of tumoral cells from the primary tumor may be mediated by attenuating EMT (54). The epithelial cell marker E-cadherin, and the mesenchymal cell markers N-cadherin and MMP9 are primary EMT markers (52,55). The results of the present study revealed that FA2H overexpression increased the expression levels of E-cadherin and decreased the expression levels of N-cadherin and MMP9 compared with the control-plasmid group.…”