Ataxin-1 regulates epithelial-mesenchymal transition of cervical cancer cells.

A-Ram Kang,Jesang Ko,Seongman Kang,Hyoung-Tae An

doi:10.18632/oncotarget.15319

Abstract

The mutant form of the protein ataxin-1 (ATXN1) causes the neurodegenerative disease spinocerebellar ataxia type-1. Recently, ATXN1 was reported to enhance E-cadherin expression in the breast cancer cell line MCF-7, suggesting a potential association between ATXN1 and cancer development. In the present study, we discovered a novel mechanism through which ATXN1 regulates the epithelial–mesenchymal transition (EMT) of cancer cells. Hypoxia-induced upregulation of the Notch intracellular domain expression decreased ATXN1 expression via MDM2-associated ubiquitination and degradation. In cervical cancer cells, ATXN1 knockdown induced EMT by directly regulating Snail expression, leading to matrix metalloproteinase activation and the promotion of cell migration and invasion. These findings provide insights into a novel mechanism of tumorigenesis and will facilitate the development of new and more effective therapies for cancer.

Highlights

The 98-kDa, 816 amino acid-long soluble protein ataxin-1 (ATXN1) is found predominantly in the nuclei of neurons and may function as a transcriptional regulator [1]
We think that DAPT GSI should be not strong enough to completely inhibit the γ-secretase proteins, since Notch intracellular domain (NICD) was still produced and ATXN1 levels still decreased upon hypoxia in the presence of DAPT
The recruitment of ATXN1 to the Snail promoter was abrogated in the presence of NICD. These results suggest that ATXN1 knockdown induces epithelial– mesenchymal transition (EMT) in cervical cancer cell lines and that the Snail promoter is a direct target of ATXN1

Summary

Introduction

The 98-kDa, 816 amino acid-long soluble protein ataxin-1 (ATXN1) is found predominantly in the nuclei of neurons and may function as a transcriptional regulator [1]. The mutant form of ATXN1, which contains an expanded polyglutamine tract, causes spinocerebellar ataxia type-1 (SCA1). Several structural domains of ATXN1 have been identified, including the self-association region and AXH domain, which facilitate protein–protein interactions, and an RNA-binding motif [2, 3]. The AXH domain of ATXN1, which is evolutionarily conserved, may be essential for the pathogenesis of SCA1 in conjunction with the expanded polyglutamine tract [4, 5]. ATXN1 is a component of the Notch signaling pathway [6]. Notch is cleaved via a cascade of proteolytic cleavage steps by the metalloprotease tumor necrosis factorα-converting enzyme and γ-secretase, releasing the Notch intracellular domain (NICD). NICD subsequently translocates into the nucleus and interacts with the transcriptional activator CSL (CBF1/RBPJk in vertebrates, Suppressor of Hairless in Drosophila, Lag-1 in Caenorhabditis elegans) to convert the latter into a potent transcriptional activator of Snail [7–10]

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