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

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.

Prognostic and therapeutic value of disruptor of telomeric silencing-1-like (DOT1L) expression in patients with ovarian cancer

“…Furthermore, a few recent publications have reported that DOT1L plays crucial roles not only in leukemia, but also in solid tumors, such as breast cancer, esophageal squamous cell carcinoma, colorectal cancer, prostate cancer, and gastric cancer [13–19]. Moreover, DOT1L inhibitors have shown effective suppression of proliferation, migration, and invasion of breast cancer [20]. …”

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p

“…Recent studies have uncovered novel epigenetic mechanisms such as methylation of lysine in histones to preferentially amplify pro-tumorigenic signaling of cancer cells to EMT (16–19). In particular, a striking correlation between TGF-β1 and EZH2, a histone methyl transferase enzyme in the Polycomb Repressive Complex 2 (PRC2) involved in silencing of genes via H3K27Me, was recognized to regulate EMT (20, 21).…”

Targeting of cancer stem cells by inhibitors of DNA and histone methylation

“…This effect on tumor growth is not fully understood. The inhibition of DOT1L (the histone methyltransferase for H3K79me3, a gene activation marker) by DZNep suppresses the growth of breast carcinoma cells [50]. Aberrant methylation of H3K79me3 by DOT1L in MLL-rearranged leukemia can result in the activation of HoxA genes, thus promoting leukemic cell proliferation [51].…”