Phosphorylation of ezh2 at t416 by cdk2 contributes to the malignancy of triple negative breast cancers

Cheng Chieh Yang, Adam Labaff, Yongkun Wei, Lei Nie, Weiya Xia, Longfei Huo, Hirohito Yamaguchi, Yi Hsin Hsu, Jennifer L. Hsu, Dongping Liu, Jingyu Lang, Yi Du, Huang Chun Lien, Long Yuan Li, Rong Deng, Li Chuan Chan, Jun Yao, Celina G. Kleer, Gabriel N. Hortobagyi, Mien Chie Hung

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Triple-negative breast cancer (TNBC), which is closely related to basal-like breast cancer, is a highly aggressive subtype of breast cancer that initially responds to chemotherapy but eventually develops resistance. This presents a major clinical challenge as there are currently no effective targeted therapies available due to its lack of HER2 and estrogen receptor expression. Here, we show that cyclin E and the enhancer of zeste 2 (EZH2) are closely co-expressed in TNBC patients, and cyclin E/CDK2 phosphorylates EZH2 at T416 (pT416-EZH2) in vivo. Phosphorylation of EZH2 at T416 enhances the ability of EZH2 to promote TNBC cell migration/invasion, tumorsphere formation, and in vivo tumor growth. In addition, high pT416-EZH2 correlates with poorer survival in TNBC patients. These findings suggest that pT416 has the potential to serve as a therapeutic biomarker for the aggressive forms of breast cancer and provide a rationale for the use of CDK2 inhibitors to treat TNBC.

Original languageEnglish (US)
Pages (from-to)1009-1020
Number of pages12
JournalAmerican Journal of Translational Research
Volume7
Issue number6
StatePublished - Feb 25 2015
Externally publishedYes

Keywords

  • CDK2
  • EZH2
  • Phosphorylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Clinical Biochemistry
  • Cancer Research

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    Yang, C. C., Labaff, A., Wei, Y., Nie, L., Xia, W., Huo, L., Yamaguchi, H., Hsu, Y. H., Hsu, J. L., Liu, D., Lang, J., Du, Y., Lien, H. C., Li, L. Y., Deng, R., Chan, L. C., Yao, J., Kleer, C. G., Hortobagyi, G. N., & Hung, M. C. (2015). Phosphorylation of ezh2 at t416 by cdk2 contributes to the malignancy of triple negative breast cancers. American Journal of Translational Research, 7(6), 1009-1020.