Journal Article

BET bromodomain inhibitors regulate keratinocyte plasticity

Carbone, Walter, Dales, Natalie, Turner, Jonathan, Schutzius, Gabi, Beyerbach, Armin, Bergling, Sebastian, Thomas, Jason R., Richards, Shola M., Ruffner, Heinz, Guagnano, Vito, Renner, Steffen, Zimmerlin, Alfred, Faller, Michael, Frederiksen, Mathias, Leroy, Nelly, Schirle, Markus, Sahambi, Sukhdeep, Lohmann, Felix, Manley, Paul W., Berwick, Amy, Bouchez, Laure, Kirkland, Susan, Drueckes, Peter, Zink, Florence, Bouwmeester, Tewis, Reynolds, Aimee, Driver, Vickie, Klopp, Julia, Roma, Guglielmo, Hemmig, Rene, Rueeger, Heinrich, Keller, Caroline Gubser, Tortelli, Federico, Cotesta, Simona, Aebi, Alexandra, Vaupel, Andrea, Nigsch, Florian, Salathe, Adrian, Fuchs, Florian, Terranova, Remi, Li, Jun, Kolter, Christian, Tiedt, Ralph, Louis, Malvina, Blank, Jutta, Grandjean, Frederic, Jennings, Lori L., Gruber, Viktoria, Dimitri, Chris, Bonenfant, Debora, Tarsa, Peter

2021

Overview

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. A chemical screen identified BET bromodomain inhibitors as promoters of keratinocyte regenerative function and skin wound healing. Specifically, low-dose transient treatment with BET inhibitors imposes an activated, migratory state in keratinocytes.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/337/458 / 631/532 / 631/92/507 / 631/92/613 / Animals / Biochemical Engineering / Biochemistry / Bioorganic Chemistry / Cell Biology / Cell Cycle Proteins - antagonists & inhibitors / Cell Cycle Proteins - genetics / Cell Cycle Proteins - metabolism / Chemistry / Chemistry and Materials Science / Chemistry/Food Science / Disease Models, Animal / Epidermis / Epidermis - drug effects / Epidermis - metabolism / Epidermis - pathology / Fluorescence Resonance Energy Transfer / Gene Expression Regulation / High-Throughput Screening Assays / Humans / Inhibitors / Keratinocytes / Keratinocytes - drug effects / Keratinocytes - metabolism / Keratinocytes - pathology / Male / Mice / Mice, Inbred C57BL / Plastic properties / Plasticity / 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 / Regulators / Skin / 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 / Ulcers / Wound healing / Wounds, Nonpenetrating - drug therapy / Wounds, Nonpenetrating - genetics / Wounds, Nonpenetrating - metabolism / Wounds, Nonpenetrating - pathology