BET bromodomain inhibitors regulate keratinocyte plasticity

Nat Chem Biol. 2021 Mar;17(3):280-290. doi: 10.1038/s41589-020-00716-z. Epub 2021 Jan 18.

Abstract

Although most acute skin wounds heal rapidly, non-healing skin ulcers represent an increasing and substantial unmet medical need that urgently requires effective therapeutics. Keratinocytes resurface wounds to re-establish the epidermal barrier by transitioning to an activated, migratory state, but this ability is lost in dysfunctional chronic wounds. Small-molecule regulators of keratinocyte plasticity with the potential to reverse keratinocyte malfunction in situ could offer a novel therapeutic approach in skin wound healing. Utilizing high-throughput phenotypic screening of primary keratinocytes, we identify such small molecules, including bromodomain and extra-terminal domain (BET) protein family inhibitors (BETi). BETi induce a sustained activated, migratory state in keratinocytes in vitro, increase activation markers in human epidermis ex vivo and enhance skin wound healing in vivo. Our findings suggest potential clinical utility of BETi in promoting keratinocyte re-epithelialization of skin wounds. Importantly, this novel property of BETi is exclusively observed after transient low-dose exposure, revealing new potential for this compound class.

MeSH terms

  • Animals
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Disease Models, Animal
  • Epidermis / drug effects*
  • Epidermis / metabolism
  • Epidermis / pathology
  • Fluorescence Resonance Energy Transfer
  • Gene Expression Regulation
  • High-Throughput Screening Assays
  • Humans
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Keratinocytes / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Primary Cell Culture
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Precursors / antagonists & inhibitors
  • Protein Precursors / genetics
  • Protein Precursors / metabolism
  • Re-Epithelialization / drug effects*
  • Re-Epithelialization / genetics
  • Skin Ulcer / drug therapy*
  • Skin Ulcer / genetics
  • Skin Ulcer / metabolism
  • Skin Ulcer / pathology
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic
  • Wounds, Nonpenetrating / drug therapy*
  • Wounds, Nonpenetrating / genetics
  • Wounds, Nonpenetrating / metabolism
  • Wounds, Nonpenetrating / pathology

Substances

  • BRD4 protein, human
  • Cell Cycle Proteins
  • Protein Isoforms
  • Protein Precursors
  • Small Molecule Libraries
  • Transcription Factors
  • involucrin