Ataxin-1 is involved in tumorigenesis of cervical cancer cells via the EGFR-RAS-MAPK signaling pathway.

A-Ram Kang,Jesang Ko,Eui-Ju Choi,Seongman Kang,Hyoung-Tae An

doi:10.18632/oncotarget.21814

Abstract

Ataxin-1 (ATXN1) is a coregulator protein within which expansion of the polyglutamine tract causes spinocerebellar ataxia type 1, an autosomal dominant neurodegenerative disorder. Previously, we reported that ATXN1 regulates the epithelial–mesenchymal transition of cervical cancer cells. In the present study, we demonstrate that ATXN1 is involved in cervical cancer tumorigenesis by promoting the proliferation of human cervical cancer cells. Chromatin immunoprecipitation assays showed that ATXN1 bound to the promoter region within cyclin D1 and activated cyclin D1 transcription, resulting in cell proliferation. ATXN1 promoted cyclin D1 expression through the EGFR–RAS–MAPK signaling pathway. Mouse xenograft tumorigenicity assays showed that ATXN1 downregulation inhibited tumorigenesis in cervical cancer cell lines in nude mice. Human cervical cancer tissue microarrays and immunohistochemical techniques showed that ATXN1 was significantly upregulated in many such tissues. Our results suggest that ATXN1 plays an important role in cervical cancer tumorigenesis and is a prognostic marker for cervical cancer.

Highlights

Ataxin-1 (ATXN1) is an evolutionarily conserved, 98-kDa protein involved in transcriptional regulation and cell signaling
We demonstrate that ATXN1 is overexpressed in cervical cancer cells; this overexpression could have been induced by factors such as EGF and that EGF-mediated ATXN1 induction depends on the activation of the epidermal growth factor receptor (EGFR)–RAS–MAPK pathway
Cyclin D1 promoter activity is stronger in SiHa cells expressing ATXN1(30Q) than in SiHa cells expressing ATXN1(82Q). These results indicate that ATXN1 promotes the growth of cervical cancer cells through the upregulation of cyclin D1 expression, which is required for progression from the G1 phase of the cell cycle

Summary

Introduction

Ataxin-1 (ATXN1) is an evolutionarily conserved, 98-kDa protein involved in transcriptional regulation and cell signaling. Soluble ATXN1 interacts with many proteins, including Capicua, Notch, Sp1, DRD2, WNT and PP2A [1,2,3,4]. ATXN1 seems to be involved in RNA processing owing to its interaction with RBM17 [5, 6]. ATXN1 regulates the cerebellar bioenergetics proteome through the GSK3b-mTOR pathway, which is altered in spinocerebellar ataxia type 1 (SCA1), an autosomal dominant neurodegenerative disorder [7]. An expansion of the polyglutamine tract within ATXN1 causes SCA1 [8, 9]. It has been recently reported that ATXN1 regulates the epithelial–mesenchymal transition of cervical cancer cells [10]

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