Phosphorylation of EZH2 at T416 by CDK2 contributes to the malignancy of triple negative breast cancers.
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.
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030 ; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston Houston, Texas 77030.
Cheng-Chieh
CC
Yang
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030 ; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston Houston, Texas 77030.
Adam
A
LaBaff
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Yongkun
Y
Wei
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Lei
L
Nie
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Weiya
W
Xia
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Longfei
L
Huo
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Hirohito
H
Yamaguchi
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Yi-Hsin
YH
Hsu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030 ; Center for Molecular Medicine, and Graduate Institute of Cancer Biology, China Medical University Taichung 404, Taiwan ; Department of Biotechnology, Asia University Taichung 413, Taiwan.
Jennifer L
JL
Hsu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Dongping
D
Liu
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Jingyu
J
Lang
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Yi
Y
Du
Department of Pathology, College of Medicine, National Taiwan University Taipei 106, Taiwan.
Huang-Chun
HC
Lien
Center for Molecular Medicine, and Graduate Institute of Cancer Biology, China Medical University Taichung 404, Taiwan ; Department of Biotechnology, Asia University Taichung 413, Taiwan.
Long-Yuan
LY
Li
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Rong
R
Deng
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030 ; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston Houston, Texas 77030.
Li-Chuan
LC
Chan
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Jun
J
Yao
Department of Pathology, University of Michigan Medical School Ann Arbor, Michigan 48109.
Celina G
CG
Kleer
Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030.
Gabriel N
GN
Hortobagyi
Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center Houston, Texas 77030 ; Graduate School of Biomedical Sciences, The University of Texas Health Science Center at Houston Houston, Texas 77030 ; Center for Molecular Medicine, and Graduate Institute of Cancer Biology, China Medical University Taichung 404, Taiwan ; Department of Biotechnology, Asia University Taichung 413, Taiwan.
Mien-Chie
MC
Hung
CDK2; EZH2; phosphorylation