MKL1 Mediates TGF-β Induced RhoJ Transcription to Promote Breast Cancer Cell Migration and Invasion.

Baoyu Chen,Yibiao Yuan,Mengzhu Yang,Lina Sun,Yong Xu,Junliang Chen,Yongmei Yin

doi:10.3389/fcell.2020.00832

Abstract

Differential regulation of gene transcription contributes to cancer metastasis. We investigated the involvement of a Rho GTPase (RhoJ) in breast cancer metastasis focusing on the mechanism underlying RhoJ trans-activation by pro-metastatic cues. We report that expression of RhoJ was up-regulated in malignant breast cancer cells compared to more benign ones. Higher RhoJ expression was also detected in human breast cancer biopsy specimens of advanced stages. RhoJ depletion attenuated breast cancer cell migration and invasion in vitro and metastasis in vivo. The pro-metastatic stimulus TGF-β activated RhoJ via megakaryocytic leukemia 1 (MKL1). MKL1 interacted with and was recruited by ETS-related gene 1 (ERG1) to the RhoJ promoter to activate transcription. In conclusion, our data delineate a novel transcriptional pathway that contributes to breast cancer metastasis. Targeting the ERG1-MKL1-RhoJ axis may be considered as a reasonable approach to treat malignant breast cancer.

Highlights

Breast cancer is the most commonly diagnosed cancer in women worldwide
To define a broad role for RhoJ in breast cancer metastasis, we examined the expression levels of different Rho GTPases in different breast cancer cell lines
We observed in patients with advanced stages of breast cancer elevated RhoJ mRNA expression compared to patients with a less malignant phenotype (Figure 1C)

Summary

Introduction

Breast cancer is the most commonly diagnosed cancer in women worldwide. The growth in the understanding of its molecular pathogenesis notwithstanding, breast cancer remains the leading cause of cancer-related deaths in female patients claiming over 600,000 lives each year (Bray et al, 2018). Metastatic breast cancers are characterized by aggressive behaviors of proliferation, migration, and invasion, resistance to cytotoxic chemotherapeutic drugs, and evasion of immune surveillance. Elucidation of the mechanisms whereby breast cancer cells acquire these malignant traits holds the key to novel therapeutic solutions against this malicious disease. Accompanying the transition of a benign breast cancer cell to a more malignant one is the alteration of its transcriptome (Kwa et al, 2017). Breast cancer cells, stimulated by a pro-metastatic cue (e.g., transforming growth factor), shed the expression of epithelial signature

Methods

Results

Conclusion