SMAD3 promotes ELK3 expression following transforming growth factor β‑mediated stimulation of MDA‑MB231 cells

Abstract

Transforming growth factor-β (TGFβ) is a secreted cytokine whose aberrant spatiotemporal expression is related to cancer progression and metastasis. While TGFβ acts as a tumor suppressor in normal and premalignant stages, TGFβ functions as a tumor promoter during the malignant phases of tumor progression by prompting cancer cells to undergo epithelial-mesenchymal transition (EMT), which enhances tumor cell invasion and ultimately promotes metastasis to other organs. Extensive studies have been performed to uncover the molecular and cellular mechanisms underlying TGFβ inducing EMT in cancer cells. Here, we suggested that ELK3, which encodes a protein that orchestrates invasion and metastasis of triple negative breast cancer cells, is a downstream target of TGFβ-SMAD3 in MDA-MB231 cells. ELK3 expression was increased in a time-dependent manner upon TGFβ treatment. Chemical and molecular inhibition of the TGFβ receptor blocked the ability of TGFβ to induce ELK3 expression. Small interfering RNA-mediated suppression analysis revealed that SMAD3 induces TGFβ signaling to express ELK3. Moreover, the results of the luciferase reporter assay and chromatin immunoprecipitation analysis showed that SMAD3 directly binds to the SMAD-binding element on the promoter of ELK3 to activate gene expression following TGFβ stimulation. We concluded that ELK3 is a novel downstream target of TGFβ-SMAD3 signaling in aggressive breast cancer cells.

Epithelial–mesenchymal transition and its transcription factors

“…of liver fibrosis (208)(209)(210). Indeed, Elk3 expression was upregulated in breast cancer cells and liver cells following TGFβ treatment.…”

“…Indeed, Elk3 expression was up-regulated in breast cancer cells and liver cells following TGFβ treatment. Subsequently, SMAD3 and ZEB1 both were found to directly regulate Elk3 expression by binding to its promoter region [ 209 , 210 ]. ZEB1 was further shown to form complex with Elk3 and suppress E-Cadherin expression [ 209 ].…”