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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

Antihistamine Drug Ebastine Inhibits Cancer Growth by Targeting Polycomb Group Protein EZH2

Qiaqia Li, Kilia Y. Liu, Qipeng Liu, Guangyu Wang, Weihua Jiang, Qingshu Meng, Yang Yi, Yongyong Yang, Rui Wang, Sen Zhu, Chao Li, Longxiang Wu, Dongyu Zhao, Lin Yan, Lili Zhang, Jung-Sun Kim, Xiongbing Zu, Anthony J. Kozielski, Wei Qian, Jenny C. Chang, Akash Patnaik, Kaifu Chen and Qi Cao
Qiaqia Li
1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
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Kilia Y. Liu
1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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Qipeng Liu
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
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Guangyu Wang
3Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, Texas.
4Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
5Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York.
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Weihua Jiang
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
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Qingshu Meng
1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
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Yang Yi
1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
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Yongyong Yang
1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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Rui Wang
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
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Sen Zhu
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
4Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
5Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York.
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Chao Li
1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
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Longxiang Wu
1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
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Dongyu Zhao
3Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, Texas.
4Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
5Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York.
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Lin Yan
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
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Lili Zhang
4Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
5Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York.
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Jung-Sun Kim
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
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Xiongbing Zu
6Department of Urology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Anthony J. Kozielski
7Houston Methodist Cancer Center, Houston, Texas.
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Wei Qian
7Houston Methodist Cancer Center, Houston, Texas.
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Jenny C. Chang
7Houston Methodist Cancer Center, Houston, Texas.
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Akash Patnaik
8Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, Illinois.
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Kaifu Chen
3Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, Texas.
4Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
5Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York.
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  • For correspondence: qi.cao@northwestern.edu kchen2@houstonmethodist.org
Qi Cao
1Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
2Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
7Houston Methodist Cancer Center, Houston, Texas.
9Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
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  • For correspondence: qi.cao@northwestern.edu kchen2@houstonmethodist.org
DOI: 10.1158/1535-7163.MCT-20-0250 Published October 2020
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Abstract

Enhancer of zester homolog 2 (EZH2), a histone lysine methyltransferase and the catalytic component of polycomb repressive complex 2, has been extensively investigated as a chromatin regulator and a transcriptional suppressor by methylating H3 at lysine 27 (H3K27). EZH2 is upregulated or mutated in most cancers, and its expression levels are negatively associated with clinical outcomes. However, the current developed small-molecule inhibitors targeting EZH2 enzymatic activities could not inhibit the growth and progression of solid tumors. Here, we discovered an antihistamine drug, ebastine, as a novel EZH2 inhibitor by targeting EZH2 transcription and subsequently downregulating EZH2 protein level and H3K27 trimethylation in multiple cancer cell lines at concentrations below 10 μmol/L. The inhibition of EZH2 by ebastine further impaired the progression, migration, and invasiveness of these cancer cells. Overexpression of Ezh2 wild-type and its mutant, H689A (lacking methyltransferase activity), rescued the neoplastic properties of these cancer cells after ebastine treatment, suggesting that EZH2 targeted by ebastine is independent of its enzymatic function. Next-generation RNA-sequencing analysis also revealed that C4-2 cells treated with 8 μmol/L ebastine showed a gene profiling pattern similar to EZH2-knockdown C4-2 cells, which was distinctively different from cells treated with GSK126, an EZH2 enzyme inhibitor. In addition, ebastine treatment effectively reduced tumor growth and progression, and enhanced progression-free survival in triple-negative breast cancer and drug-resistant castration-resistant prostate cancer patient-derived xenograft mice. Our data demonstrated that ebastine is a novel, safe, and potent anticancer agent for patients with advanced cancer by targeting the oncoprotein EZH2.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:2023–33

  • Received March 30, 2020.
  • Revision received May 21, 2020.
  • Accepted August 5, 2020.
  • Published first August 27, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (10)
October 2020
Volume 19, Issue 10
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Antihistamine Drug Ebastine Inhibits Cancer Growth by Targeting Polycomb Group Protein EZH2
Qiaqia Li, Kilia Y. Liu, Qipeng Liu, Guangyu Wang, Weihua Jiang, Qingshu Meng, Yang Yi, Yongyong Yang, Rui Wang, Sen Zhu, Chao Li, Longxiang Wu, Dongyu Zhao, Lin Yan, Lili Zhang, Jung-Sun Kim, Xiongbing Zu, Anthony J. Kozielski, Wei Qian, Jenny C. Chang, Akash Patnaik, Kaifu Chen and Qi Cao
Mol Cancer Ther October 1 2020 (19) (10) 2023-2033; DOI: 10.1158/1535-7163.MCT-20-0250

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Antihistamine Drug Ebastine Inhibits Cancer Growth by Targeting Polycomb Group Protein EZH2
Qiaqia Li, Kilia Y. Liu, Qipeng Liu, Guangyu Wang, Weihua Jiang, Qingshu Meng, Yang Yi, Yongyong Yang, Rui Wang, Sen Zhu, Chao Li, Longxiang Wu, Dongyu Zhao, Lin Yan, Lili Zhang, Jung-Sun Kim, Xiongbing Zu, Anthony J. Kozielski, Wei Qian, Jenny C. Chang, Akash Patnaik, Kaifu Chen and Qi Cao
Mol Cancer Ther October 1 2020 (19) (10) 2023-2033; DOI: 10.1158/1535-7163.MCT-20-0250
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