Tripartite motif containing 28 (TRIM28) promotes breast cancer metastasis by stabilizing TWIST1 protein.

Chunli Wei,Yongxiang Zhao,Junjiang Fu,Md Asaduzzaman Khan,Li Zhu,Jingliang Cheng,Tao He,Boxv Zhou,Jian He,Xiaoling Lu,Dianzheng Zhang,Sufang Zhou,Hanchun Chen

doi:10.1038/srep29822

Abstract

TRIM28 regulates its target genes at both transcriptional and posttranscriptional levels. Here we report that a TRIM28-TWIST1-EMT axis exists in breast cancer cells and TRIM28 promotes breast cancer metastasis by stabilizing TWIST1 and subsequently enhancing EMT. We find that TRIM28 is highly expressed in both cancer cell lines and advanced breast cancer tissues, and the levels of TRIM28 and TWIST1 are positively correlated with the aggressiveness of breast carcinomas. Overexpression and depletion of TRIM28 up- and down-regulates the protein, but not the mRNA levels of TWIST1, respectively, suggesting that TRIM28 upregulates TWIST1 post-transcriptionally. Overexpression of TRIM28 in breast cancer cell line promotes cell migration and invasion. Knockdown of TRIM28 reduces the protein level of TWIST1 with concurrent upregulation of E-cadherin and downregulation of N-cadherin and consequently inhibits cell migration and invasion. Furthermore, Immunoprecipitation and GST pull-down assays demonstrated that TRIM28 interacts with TWIST1 directly and this interaction is presumed to protect TWIST1 from degradation. Our study revealed a novel mechanism in breast cancer cells that TRIM28 enhances metastasis by stabilizing TWIST1, suggesting that targeting TRIM28 could be an efficacious strategy in breast cancer treatment.

Highlights

Transcription factor TWIST1 plays important roles in different processes of cancer development including metastasis, generation of cancer cell stemness and drug resistance, and these characteristics make TWIST1 an oncoprotein[1,2,3]
It has been reported that tripartite motif-containing 28 (TRIM28) is capable of promoting breast cancer cell proliferation and metastatic progression[22]
Based on the role of TRIM28 in epithelial-to-mesenchymal transition (EMT), we propose that in breast cancer cells exist a TRIM28-TWIST1-EMT axis which plays an important role in breast cancer metastasis

Summary

Introduction

Transcription factor TWIST1 plays important roles in different processes of cancer development including metastasis, generation of cancer cell stemness and drug resistance, and these characteristics make TWIST1 an oncoprotein[1,2,3]. Altered expression of TWIST1 and/or hyper-methylation of its promoter regions have been implicated in the development of different cancers, including breast cancer[1,8,9]. TRIM28 is involved in the fibroblast-specific protein 1 (FSP-1)- or TGF-β-induced EMT in lung cancer[23,24] These findings together indicate that TRIM28 may be involved in EMT and EMT-associated proteins and transcript factors (EMT-TFs), such as E-cadherin, N-cadherin, TWIST1, and SNAIL1. Based on the role of TRIM28 in EMT, we propose that in breast cancer cells exist a TRIM28-TWIST1-EMT axis which plays an important role in breast cancer metastasis

Methods

Results

Conclusion