2-Hydroxyglutarate destabilizes chromatin regulatory landscape and lineage fidelity to promote cellular heterogeneity

Meena Kusi, Maryam Zand, Li Ling Lin, Meizhen Chen, Anthony Lopez, Chun Lin Lin, Chiou Miin Wang, Nicholas D. Lucio, Nameer B. Kirma, Jianhua Ruan, Tim H.M. Huang, Kohzoh Mitsuya

Research output: Contribution to journalArticlepeer-review

Abstract

The epigenome delineates lineage-specific transcriptional programs and restricts cell plasticity to prevent non-physiological cell fate transitions. Although cell diversification fosters tumor evolution and therapy resistance, upstream mechanisms that regulate the stability and plasticity of the cancer epigenome remain elusive. Here we show that 2-hydroxyglutarate (2HG) not only suppresses DNA repair but also mediates the high-plasticity chromatin landscape. A combination of single-cell epigenomics and multi-omics approaches demonstrates that 2HG disarranges otherwise well-preserved stable nucleosome positioning and promotes cell-to-cell variability. 2HG induces loss of motif accessibility to the luminal-defining transcriptional factors FOXA1, FOXP1, and GATA3 and a shift from luminal to basal-like gene expression. Breast tumors with high 2HG exhibit enhanced heterogeneity with undifferentiated epigenomic signatures linked to adverse prognosis. Further, ascorbate-2-phosphate (A2P) eradicates heterogeneity and impairs growth of high 2HG-producing breast cancer cells. These findings suggest 2HG as a key determinant of cancer plasticity and provide a rational strategy to counteract tumor cell evolution.

Original languageEnglish (US)
Article number110220
JournalCell Reports
Volume38
Issue number2
DOIs
StatePublished - Jan 11 2022
Externally publishedYes

Keywords

  • 2-hydroxyglutarate
  • DNA repair
  • breast cancer
  • cancer cell plasticity
  • chromatin CyTOF
  • epigenome fluctuation
  • lineage fidelity
  • luminal-to-basal transition
  • oncometabolite
  • single-cell epigenomics

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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