Ataxin-1 Regulates Epithelial-mesenchymal Transition of Cervical Cancer Cells

Overview

Journal Oncotarget

Specialty Oncology

Date 2017 Feb 18

PMID 28212558

Citations 23

Authors

A-Ram Kang

Hyoung-Tae An

Jesang Ko

Seongman Kang

Affiliations

Soon will be listed here.

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.

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References

Hong S, Lee S, Cho S, Kang S . UbcH6 interacts with and ubiquitinates the SCA1 gene product ataxin-1. Biochem Biophys Res Commun. 2008; 371(2):256-60. DOI: 10.1016/j.bbrc.2008.04.066. View

Goo H, Rhim H, Kang S . HtrA2/Omi influences the stability of LON protease 1 and prohibitin, proteins involved in mitochondrial homeostasis. Exp Cell Res. 2014; 328(2):456-65. DOI: 10.1016/j.yexcr.2014.07.032. View

Peinado H, Olmeda D, Cano A . Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer. 2007; 7(6):415-28. DOI: 10.1038/nrc2131. View

Sullivan R, Graham C . Hypoxia-driven selection of the metastatic phenotype. Cancer Metastasis Rev. 2007; 26(2):319-31. DOI: 10.1007/s10555-007-9062-2. View

Gonzalez D, Medici D . Signaling mechanisms of the epithelial-mesenchymal transition. Sci Signal. 2014; 7(344):re8. PMC: 4372086. DOI: 10.1126/scisignal.2005189. View

Xiao Y, Wang W, Gong D, Mao Z . γ-Secretase inhibitor DAPT attenuates intimal hyperplasia of vein grafts by inhibition of Notch1 signaling. Lab Invest. 2014; 94(6):654-62. DOI: 10.1038/labinvest.2014.58. View

Vaupel P, Mayer A . Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 2007; 26(2):225-39. DOI: 10.1007/s10555-007-9055-1. View

Pettersson S, Sczaniecka M, McLaren L, Russell F, Gladstone K, Hupp T . Non-degradative ubiquitination of the Notch1 receptor by the E3 ligase MDM2 activates the Notch signalling pathway. Biochem J. 2012; 450(3):523-36. DOI: 10.1042/BJ20121249. View

Park Y, Hong S, Kim S, Kang S . Proteasome function is inhibited by polyglutamine-expanded ataxin-1, the SCA1 gene product. Mol Cells. 2005; 19(1):23-30. View

10.

Sahlgren C, Gustafsson M, Jin S, Poellinger L, Lendahl U . Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A. 2008; 105(17):6392-7. PMC: 2359811. DOI: 10.1073/pnas.0802047105. View

11.

Kalluri R, Weinberg R . The basics of epithelial-mesenchymal transition. J Clin Invest. 2009; 119(6):1420-8. PMC: 2689101. DOI: 10.1172/JCI39104. View

12.

Yang J, Mani S, Liu Donaher J, Ramaswamy S, Itzykson R, Come C . Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 2004; 117(7):927-39. DOI: 10.1016/j.cell.2004.06.006. View

13.

Lee S, Choi D, Rhim H, Choo H, Ko Y, Kim C . PHB2 interacts with RNF2 and represses CP2c-stimulated transcription. Mol Cell Biochem. 2008; 319(1-2):69-77. DOI: 10.1007/s11010-008-9878-2. View

14.

Wang Y, Shi J, Chai K, Ying X, Zhou B . The Role of Snail in EMT and Tumorigenesis. Curr Cancer Drug Targets. 2013; 13(9):963-972. PMC: 4004763. DOI: 10.2174/15680096113136660102. View

15.

Morra L, Moch H . Periostin expression and epithelial-mesenchymal transition in cancer: a review and an update. Virchows Arch. 2011; 459(5):465-75. PMC: 3205268. DOI: 10.1007/s00428-011-1151-5. View

16.

Lin C, Tsai P, Kandaswami C, Lee P, Huang C, Hwang J . Matrix metalloproteinase-9 cooperates with transcription factor Snail to induce epithelial-mesenchymal transition. Cancer Sci. 2011; 102(4):815-27. DOI: 10.1111/j.1349-7006.2011.01861.x. View

17.

DSouza B, Meloty-Kapella L, Weinmaster G . Canonical and non-canonical Notch ligands. Curr Top Dev Biol. 2010; 92:73-129. PMC: 4286395. DOI: 10.1016/S0070-2153(10)92003-6. View

18.

Mizutani A, Wang L, Rajan H, Vig P, Alaynick W, Thaler J . Boat, an AXH domain protein, suppresses the cytotoxicity of mutant ataxin-1. EMBO J. 2005; 24(18):3339-51. PMC: 1224676. DOI: 10.1038/sj.emboj.7600785. View

19.

Gordan J, Simon M . Hypoxia-inducible factors: central regulators of the tumor phenotype. Curr Opin Genet Dev. 2007; 17(1):71-7. PMC: 3215290. DOI: 10.1016/j.gde.2006.12.006. View

20.

Imanaka N, Chen J, Griffin J . Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increased cell migration and invasion. Br J Cancer. 2009; 102(2):351-60. PMC: 2816657. DOI: 10.1038/sj.bjc.6605486. View