MRTF/SRF dependent transcriptional regulation of TAZ in breast cancer cells.

Chen-Ying Liu,Long Cui,Fusheng Guo,Siew Wee Chan,Aleksandra Toloczko,Wanjin Hong

doi:10.18632/oncotarget.7333

Abstract

Dysregulation of Hippo pathway results in activation of transcriptional co-activators YAP/TAZ in breast cancer. Previously, we showed that overexpression of TAZ in breast cancer promotes cell migration, invasion and tumorigenesis. Here, we show that upregulation of TAZ in breast cancers could also be due to dysregulation of TAZ transcription. Heregulin β1 (HRG1) increases TAZ mRNA level in breast cancer cells. TAZ is a direct target of MRTF/SRF transcriptional factors which are activated by HRG1. Both MRTF/SRF and TAZ are the important downstream effectors enhancing cell migration induced by HRG1. TAZ mRNA level is correlated with nuclear localization of MRTF in breast cancer cells and the mRNA level of MRTF/SRF direct target genes in breast cancers, indicating the correlation between MRTF/SRF activity and TAZ expression. Our results provide new insights into the transcriptional regulation of TAZ and dysregulation mechanism of TAZ in breast cancer, which could be a new therapeutic strategy for breast cancer.

Highlights

The Hippo pathway is a conserved signaling pathway regulating the organ size in mammalians [1]
TAZ is the downstream effector enhancing cell migration induced by Heregulin β1 in breast cancer cells
These results suggest that TAZ is induced and activated by Heregulin β1 (HRG1) to enhance tumorigenesis in breast cancer cells

Summary

Introduction

The Hippo pathway is a conserved signaling pathway regulating the organ size in mammalians [1]. Dysregulation of the Hippo pathway occurs in multiple cancers, including breast cancer [1]. Main components of Hippo pathway consist of the core kinases MST1/2 and LATS1/2 with their binding partners WW45 and MOB1, respectively. Activation of the Hippo pathway results in cytoplasmic retention and degradation of downstream transcriptional co-activator YAP/ TAZ, leading to the repression of TEAD-mediated transcription and inhibition of cell proliferation. Multiple extracellular stimuli have been found to regulate the Hippo pathway, including contact inhibition [2], mechanotransduction [3] and GPCR [4]. Heregulins are a group of EGFlike ligands for surface ERBB2, ERBB3 and ERBB4 which are often overexpressed in the breast cancers [5] and promote cell proliferation [6] and cell migration [7], in association with tumorigenesis and aggressive phenotypes [8]

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Conclusion