LOXL2-mediated H3K4 oxidation reduces chromatin accessibility in triple-negative breast cancer cells

Oncogene. 2020 Jan;39(1):79-121. doi: 10.1038/s41388-019-0969-1. Epub 2019 Aug 28.

Abstract

Oxidation of H3 at lysine 4 (H3K4ox) by lysyl oxidase-like 2 (LOXL2) generates an H3 modification with an unknown physiological function. We find that LOXL2 and H3K4ox are higher in triple-negative breast cancer (TNBC) cell lines and patient-derived xenografts (PDXs) than those from other breast cancer subtypes. ChIP-seq revealed that H3K4ox is located primarily in heterochromatin, where it is involved in chromatin compaction. Knocking down LOXL2 reduces H3K4ox levels and causes chromatin decompaction, resulting in a sustained activation of the DNA damage response (DDR) and increased susceptibility to anticancer agents. This critical role that LOXL2 and oxidized H3 play in chromatin compaction and DDR suggests that functionally targeting LOXL2 could be a way to sensitize TNBC cells to conventional therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Oxidoreductases / genetics*
  • Animals
  • Cell Line, Tumor
  • Chromatin / genetics*
  • DNA Damage / genetics
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Heterochromatin / genetics
  • Heterografts
  • Histone Code / genetics*
  • Histones / genetics
  • Humans
  • Lysine / genetics
  • Mice
  • Oxidation-Reduction
  • Triple Negative Breast Neoplasms / genetics*
  • Triple Negative Breast Neoplasms / pathology

Substances

  • Chromatin
  • Heterochromatin
  • Histones
  • Amino Acid Oxidoreductases
  • LOXL2 protein, human
  • Lysine