Belinostat resolves skin barrier defects in atopic dermatitis by targeting the dysregulated miR-335:SOX6 axis

J Allergy Clin Immunol. 2020 Sep;146(3):606-620.e12. doi: 10.1016/j.jaci.2020.02.007. Epub 2020 Feb 21.

Abstract

Background: Atopic dermatitis (AD) is a common chronic inflammatory skin disease. Skin barrier defects contribute to disease initiation and development; however, underlying mechanisms remain elusive.

Objective: To understand the underlying cause of barrier defect, we investigated aberrant expression of specific microRNAs (miRNAs) in AD. Delineating the molecular mechanism of dysregulated miRNA network, we focused on identification of specific drugs that can modulate miRNA expression and repair the defective barrier in AD.

Methods: A screen for differentially expressed miRNAs between healthy skin and AD lesional skin resulted in the identification of miR-335 as the most consistently downregulated miRNA in AD. Using in silico prediction combined with experimental validation, we characterized downstream miR-335 targets and elucidated the molecular pathways by which this microRNA maintains epidermal homeostasis in healthy skin.

Results: miR-335 was identified as a potent inducer of keratinocyte differentiation; it exerts this effect by directly repressing SOX6. By recruiting SMARCA complex components, SOX6 suppresses epidermal differentiation and epigenetically silences critical genes involved in keratinocyte differentiation. In AD lesional skin, miR-335 expression is aberrantly lost. SOX6 is abnormally expressed throughout the epidermis, where it impairs skin barrier development. We demonstrate that miR-335 is epigenetically regulated by histone deacetylases; a screen for suitable histone deacetylase inhibitors identified belinostat as a candidate drug that can restore epidermal miR-335 expression and rescue the defective skin barrier in AD.

Conclusion: Belinostat is of clinical significance not only as a candidate drug for AD treatment, but also as a potential means of stopping the atopic march and further progression of this systemic allergic disease.

Keywords: MicroRNA; atopic dermatitis; barrier defect; chronic inflammation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line
  • Dermatitis, Atopic / genetics
  • Dermatitis, Atopic / metabolism*
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Hydroxamic Acids / pharmacology*
  • MicroRNAs / genetics*
  • SOXD Transcription Factors / genetics
  • SOXD Transcription Factors / metabolism*
  • Skin / metabolism*
  • Sulfonamides / pharmacology*

Substances

  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • MIRN335 microRNA, human
  • MicroRNAs
  • SOX6 protein, human
  • SOXD Transcription Factors
  • Sulfonamides
  • belinostat