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BET bromodomain inhibitors regulate keratinocyte plasticity
- Source :
- Nature chemical biology. 17(3)
- Publication Year :
- 2019
-
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.
- Subjects :
- Keratinocytes
Male
Protein family
Transcription, Genetic
Phenotypic screening
Primary Cell Culture
Cell Cycle Proteins
Wounds, Nonpenetrating
Small Molecule Libraries
03 medical and health sciences
Mice
Structure-Activity Relationship
Re-Epithelialization
In vivo
Skin Ulcer
medicine
Fluorescence Resonance Energy Transfer
Animals
Humans
Protein Isoforms
Protein Precursors
Molecular Biology
030304 developmental biology
0303 health sciences
integumentary system
Epidermis (botany)
business.industry
030302 biochemistry & molecular biology
Cell Biology
In vitro
Bromodomain
High-Throughput Screening Assays
Mice, Inbred C57BL
Disease Models, Animal
medicine.anatomical_structure
Gene Expression Regulation
Cancer research
Epidermis
Keratinocyte
business
Ex vivo
Transcription Factors
Subjects
Details
- ISSN :
- 15524469
- Volume :
- 17
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Nature chemical biology
- Accession number :
- edsair.doi.dedup.....70a8580afdc9f2d099758e215f9da05e