Your browser doesn't support javascript.
loading
Antihistamine Drug Ebastine Inhibits Cancer Growth by Targeting Polycomb Group Protein EZH2.
Li, Qiaqia; Liu, Kilia Y; Liu, Qipeng; Wang, Guangyu; Jiang, Weihua; Meng, Qingshu; Yi, Yang; Yang, Yongyong; Wang, Rui; Zhu, Sen; Li, Chao; Wu, Longxiang; Zhao, Dongyu; Yan, Lin; Zhang, Lili; Kim, Jung-Sun; Zu, Xiongbing; Kozielski, Anthony J; Qian, Wei; Chang, Jenny C; Patnaik, Akash; Chen, Kaifu; Cao, Qi.
Afiliación
  • Li Q; Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Liu KY; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
  • Liu Q; Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Wang G; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
  • Jiang W; Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, Texas.
  • Meng Q; Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
  • Yi Y; Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York.
  • Yang Y; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
  • Wang R; Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Zhu S; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
  • Li C; Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Wu L; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
  • Zhao D; Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Yan L; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
  • Zhang L; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
  • Kim JS; Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
  • Zu X; Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York.
  • Kozielski AJ; Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Qian W; Center for Inflammation and Epigenetics, Houston Methodist Research Institute, Houston, Texas.
  • Chang JC; Department of Urology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
  • Patnaik A; Center for Bioinformatics and Computational Biology, Houston Methodist Research Institute, Houston, Texas.
  • Chen K; Center for Cardiovascular Regeneration, Houston Methodist Research Institute, Houston, Texas.
  • Cao Q; Department of Cardiothoracic Surgery, Weill Cornell Medicine, Cornell University, New York, New York.
Mol Cancer Ther ; 19(10): 2023-2033, 2020 10.
Article en En | MEDLINE | ID: mdl-32855270
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Butirofenonas / Proteína Potenciadora del Homólogo Zeste 2 / Antagonistas de los Receptores Histamínicos H1 Límite: Female / Humans / Male Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piperidinas / Butirofenonas / Proteína Potenciadora del Homólogo Zeste 2 / Antagonistas de los Receptores Histamínicos H1 Límite: Female / Humans / Male Idioma: En Revista: Mol Cancer Ther Asunto de la revista: ANTINEOPLASICOS Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos