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CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

ABSTRACT: Triple-negative breast cancer (TNBC), which lacks estrogen receptor ? (ER?), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ER? and converts TNBC to luminal ER?-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.

SUBMITTER: Nie L

PROVIDER: S-EPMC6841924 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

Nie Lei L Wei Yongkun Y Zhang Fei F Hsu Yi-Hsin YH Chan Li-Chuan LC Xia Weiya W Ke Baozhen B Zhu Cihui C Deng Rong R Tang Jun J Yao Jun J Chu Yu-Yi YY Zhao Xixi X Han Ye Y Hou Junwei J Huo Longfei L Ko How-Wen HW Lin Wan-Chi WC Yamaguchi Hirohito H Hsu Jung-Mao JM Yang Yi Y Pan Dean N DN Hsu Jennifer L JL Kleer Celina G CG Davidson Nancy E NE Hortobagyi Gabriel N GN Hung Mien-Chie MC

Nature communications 20191108 1

Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2<sup>T416D</sup> in mammary glands leads to tumors with TN ...[more]

PMID: 31704972

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Project description:Background:Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that lacks expression of estrogen receptor (ER) and progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2) gene. Chemotherapy remains the standard of care for TNBC treatment, but considerable patients are very resistant to chemotherapy. Mutations or aberrant upregulation of EZH2 occur frequently, and EZH2 inhibitor (EZH2i) showed some preclinic antitumor effects in TNBC. Methods:RNA-seq data of 3 TNBC cell lines either treated with 2 ?M GSK343, or stably transduced with shEHZ2, compared to untreated controls (GSE112378) were analyzed by Limma R package. The Kaplan-Meier plotter (KM plotter) database was used to assess the relevance of FOSB mRNA expression to relapse-free survival (RFS) in TNBC. Cell number counting and colony formation assays were used to detect the biological effect of FOSB on the growth of TNBC cells in vitro. The effect of FOSB on TNBC tumor growth in vivo was investigated in a mice tumor xenograft model. Luciferase reporter and chromatin immunoprecipitation (Chip) assays were used to determine the regulatory roles of C/EBP? on FOSB expression. Results:We found that FOSB, a member of the activator protein-1 complex, was a direct downstream target of EZH2. FOSB was significantly decreased in TNBC samples and associated with better relapse-free survival (RFS). EZH2-mediated histone 3 trimethylated on lysine 27 (H3K27me3), a marker of silent chromatin conformation, at the FOSB promoter inhibited it expression. Depletion of FOSB in TNBC cells promoted cell proliferation in vitro and tumor growth in vitro by inactivating the p53 pathway and conferred resistant to EZH2 inhibitor (EZH2i). Mechanistically, EZH2i promotes the shift from H3K27me3 to H3K27ac at the FOSB promoter, and recruits the transcription factor C/EBP? to activate FOSB gene transcription. Conclusion:Together, our results suggest that EZH2-mediated epigenetic inactivation of FOSB promotes TNBC expression and demonstrate that reactivation of FOSB expression by C/EBP? underlies the anti-TNBC action of EZH2is.

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CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

Publications

CDK2-mediated site-specific phosphorylation of EZH2 drives and maintains triple-negative breast cancer.

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