Oncotarget

Research Papers:

Inhibition of histone H3K79 methylation selectively inhibits proliferation, self-renewal and metastatic potential of breast cancer

Li Zhang _, Lisheng Deng, Fengju Chen, Yuan Yao, Bulan Wu, Liping Wei, Qianxing Mo and Yongcheng Song

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Oncotarget. 2014; 5:10665-10677. https://doi.org/10.18632/oncotarget.2496

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Abstract

Li Zhang1, Lisheng Deng1, Fengju Chen2, Yuan Yao1, Bulan Wu1, Liping Wei1, Qianxing Mo2,3, Yongcheng Song1,2

1Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA

2Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA

3Department of Medicine, Section of Hematology/Oncology, Baylor College of Medicine, Houston, TX 77030, USA

Correspondence to:

Yongcheng Song, e-mail: ysong@bcm.edu

Keywords: DOT1L, histone methylation, inhibitor, breast cancer, cancer stem cell

Received: May 30, 2014     Accepted: September 16, 2014     Published: November 10, 2014

ABSTRACT

Histone lysine methylation regulates gene expression and cancer initiation. Bioinformatics analysis suggested that DOT1L, a histone H3-lysine79 (H3K79) methyltransferase, plays a potentially important role in breast cancer. DOT1L inhibition selectively inhibited proliferation, self-renewal, metastatic potential of breast cancer cells and induced cell differentiation. In addition, inhibitors of S-adenosylhomocysteine hydrolase (SAHH), such as neplanocin and 3-deazaneplanocin, also inhibited both H3K79 methylation and proliferation of breast cancer cells in vitro and in vivo. The activity of SAHH inhibitors was previously attributed to inhibition of H3K27 methyltransferase EZH2. However, inhibition of EZH2 by a specific inhibitor did not contribute to cell death. SAHH inhibitors had only weak activity against H3K27 methylation and their activity is therefore mainly due to DOT1L/H3K79 methylation inhibition. Overall, we showed that DOT1L is a potential drug target for breast cancer.


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