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

Oncotarget. 2014 Nov 15;5(21):10665-77. doi: 10.18632/oncotarget.2496.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine / analogs & derivatives
  • Adenosine / pharmacology
  • Animals
  • Apoptosis / drug effects
  • Blotting, Western
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology*
  • Cell Cycle / drug effects
  • Cell Differentiation / drug effects
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • DNA Methylation*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Flow Cytometry
  • Histone-Lysine N-Methyltransferase
  • Histones / chemistry*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Lysine*
  • Methyltransferases / antagonists & inhibitors*
  • Methyltransferases / genetics
  • Methyltransferases / metabolism
  • Mice
  • Mice, Nude
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Enzyme Inhibitors
  • Histones
  • RNA, Messenger
  • 3-deazaneplanocin
  • neplanocin A
  • DOT1L protein, human
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Lysine
  • Adenosine

Associated data

  • GEO/GSE56630