Downregulation of CHIP promotes ovarian cancer metastasis by inducing Snail-mediated epithelial-mesenchymal transition.

Sun Mi Park ,Na Hyun Kim,Cheol Hwangbo,Eun Mi Hwang,Hoseok Song,Kwang Dong Kim,Bok Im Cho,Jong In Yook,Hyeontak Han,Hee Jun Cho,Jeong‐Doo Heo ,In Kyu Kim ,Hyo Jin Kim ,Ki Jun Ryu ,Jae Yong Park ,Hye-Min Kim ,Seon Hee Kim ,Keun Seok Hong ,Seung Ho Park ,Min-Ju Kim ,Ji Myong Yoo

doi:10.1002/1878-0261.12485

Abstract

The epithelial–mesenchymal transition (EMT) plays a pivotal role in the conversion of early‐stage tumors into invasive malignancies. The transcription factor Snail, an extremely unstable protein whose subcellular levels are regulated by many E3 ubiquitin ligases, promotes EMT as well as associated pathological characteristics including migration, invasion, and metastasis. Through yeast two‐hybrid screening, we identified the carboxyl terminus of Hsc70‐interacting protein (CHIP) as a novel Snail ubiquitin ligase that interacts with Snail to induce ubiquitin‐mediated proteasomal degradation. Inhibition of CHIP expression increases Snail protein levels, induces EMT, and enhances in vitro migration and invasion as well as in vivo metastasis of ovarian cancer cells. In turn, Snail depletion abrogates all phenomena induced by CHIP depletion. Finally, Snail and CHIP expression is inversely correlated in ovarian tumor tissues. These findings establish the CHIP–Snail axis as a post‐translational mechanism of EMT and cancer metastasis regulation.

Highlights

The majority of cancer deaths are attributable to the local invasion and distant metastasis of tumor cells (Wan et al, 2013)
Among the positive clones independently isolated from the HeLa cell cDNA library, we focused on carboxyl terminus of Hsc70-interacting protein (CHIP) because this protein has been identified as a tumor suppressor that can induce the ubiquitylation and degradation of several oncogenic proteins (Jang et al, 2011; Kajiro et al, 2009; Kao et al, 2014; Paul et al, 2013; Tateishi et al, 2004; Wang et al, 2013; Xu et al, 2002)
We found that the two truncated forms of Snail, Snail-DSNAG and Snail-DZF, with the HDACBD and the DNA-binding domain (BD) deleted, respectively, retain the ability to associate with CHIP to the same extent as Snail-WT (Fig. 1F)

Summary

Introduction

The majority of cancer deaths are attributable to the local invasion and distant metastasis of tumor cells (Wan et al, 2013). Epithelial cells initially lose apical–basal polarity and cell–cell contact while shifting to a mesenchymal phenotype (Ikenouchi et al, 2003). This loss of epithelial features is often accompanied by increased cell motility and expression of mesenchymal genes, a process that is collectively referred to as the epithelial–mesenchymal transition (EMT) and considered a key step during the progression of tumors toward metastasis (Savanger, 2001; Thiery et al, 2009). EMT regulators, which likely play important roles in cancer progression, have been extensively studied One such regulator is the zinc finger protein Snail, which induces EMT via the direct repression of E-cadherin transcription during development or tumor progression. The association of a loss of E-cadherin expression in tumors with poor clinical outcomes has led to the use of E-cadherin repressors as markers of malignancy (Nieto, 2002; Thiery, 2002)

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Results

Discussion

Conclusion