Theranostics 2019; 9(3):761-777. doi:10.7150/thno.29520

Research Paper

Epigenetic Co-Deregulation of EZH2/TET1 is a Senescence-Countering, Actionable Vulnerability in Triple-Negative Breast Cancer

Yong Yu1*, Jingjing Qi2,3*, Jieyi Xiong1*, Liping Jiang3*, Di Cui3, Junlin He3,6, Ping Chen3,7, Lianjie Li1,3, Chenjie Wu3, Tonghui Ma3, Su Shao3,8, Jianjun Wang3,8, Dansong Yu3,9, Bing Zhou3,4, Dongsheng Huang3,5, Clemens A. Schmitt1,10,11✉, Ran Tao3,5✉

1. Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, 13125 Berlin, Germany
2. Department of Medical Oncology, Sun Yat-Sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, 510060 Guangzhou, China
3. Center for Clinical Medical Research, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, 310014 Hangzhou, China
4. Department of Cardiothoracic Surgery, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, 310014 Hangzhou, China
5. Department of Hepatobiliary-Pancreatic Surgery, Affiliated Zhejiang Provincial People's Hospital, Hangzhou Medical School, 310014 Hangzhou, China
6. Department of Breast Surgery, Hangzhou Municipal Hospital of Traditional Chinese Medicine, 310007 Hangzhou, China
7. Department of Gynecology, Shaoxing 2nd People's Hospital, 312000 Shaoxing, China
8. Department of Surgery, Chun'an 1st People's Hospital, 311700 Hangzhou, China
9. Department of Surgery, Ningbo Li Hui Li Hospital, 315041 Ningbo, China
10. Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health; Medical Department of Hematology, Oncology and Tumor Immunology, Virchow Campus, and Molekulares Krebsforschungszentrum, 13353 Berlin, Germany
11. Deutsches Konsortium für Translationale Krebsforschung (German Cancer Consortium), Partner site Berlin, Germany
*These authors contributed equally to this work.

Abstract

Triple-negative breast cancer (TNBC) cells lack the expression of ER, PR and HER2. Thus, TNBC patients cannot benefit from hormone receptor-targeted therapy as non-TNBC patients, but can only receive chemotherapy as the systemic treatment and have a worse overall outcome. More effective therapeutic targets and combination therapy strategies are urgently needed to improve the treatment effectiveness.

Methods: We analyzed the expression levels of EZH2 and TET1 in TCGA and our own breast cancer patient cohort, and tested their correlation with patient survival. We used TNBC and non-TNBC cell lines and mouse xenograft tumor model to unveil novel EZH2 targets and investigated the effect of EZH2 inhibition or TET1 overexpression in cell proliferation and viability of TNBC cells.

Results: In TNBC cells, EZH2 decreases TET1 expression by H3K27me3 epigenetic regulation and subsequently suppresses anti-tumor p53 signaling pathway. Patients with high EZH2 and low TET1 presented the poorest survival outcome. Experimentally, targeting EZH2 in TNBC cells with specific inhibitor GSK343 or shRNA genetic approach could induce cell cycle arrest and senescence by elevating TET1 expression and p53 pathway activation. Using mouse xenograft model, we have tested a novel therapy strategy to combine GSK343 and chemotherapy drug Adriamycin and could show drastic and robust inhibition of TNBC tumor growth by synergistic induction of senescence and apoptosis.

Conclusions: We postulate that the well-controlled dynamic pathway EZH2-H3K27me3-TET1 is a novel epigenetic co-regulator module and provide evidence regarding how to exploit it as a novel therapeutic target via its pivotal role in senescence and apoptosis control. Of clinical and therapeutic significance, the present study opens a new avenue for TNBC treatment by targeting the EZH2-H3K27me3-TET1 pathway that can modulate the epigenetic landscape.

Keywords: cellular senescence, epigenetic co-deregulation, EZH2, TET1, TNBC

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How to cite this article:
Yu Y, Qi J, Xiong J, Jiang L, Cui D, He J, Chen P, Li L, Wu C, Ma T, Shao S, Wang J, Yu D, Zhou B, Huang D, Schmitt CA, Tao R. Epigenetic Co-Deregulation of EZH2/TET1 is a Senescence-Countering, Actionable Vulnerability in Triple-Negative Breast Cancer. Theranostics 2019; 9(3):761-777. doi:10.7150/thno.29520. Available from http://www.thno.org/v09p0761.htm