Current Status of Healthy Human Skin Models: Can Histone Deacetylase Inhibitors Potentially Improve the Present Replacement Models?

Abstract

Histone deacetylase inhibitors (HDACi), a relatively new group of epigenetic agents, are being investigated as powerful chemotherapeutics because of their antiproliferative and prodifferentiation effects both in vitro and in vivo, in various tumor cell lines. Only little is known with respect to their effects on normal cells. Yet, to understand tissue pathology and evaluate potential effects of new chemical entities in tissue homeostasis, insight into the physiology of healthy tissue is necessary. Therefore, this review addresses the effects of HDACi on healthy human primary skin cell cultures and three-dimensional epidermal models. In general, HDACi exert an effect on both the epidermal morphology and differentiation process of human skin. The latter is manifested through cell cycle arrest, disorganization of the basal layer, thinning of the stratum spinosum and thickening of the stratum corneum, reorganization of the cytoskeleton and increased formation of cornified envelopes. This overview shows that, although only a limited number of reports exist, these molecules might be an interesting tool for the development and study of new human skin models.

Repurposing Belinostat for Alleviation of Atopic Dermatitis

“…This miR-335 upregulation occurs in tandem with increased abundance of differentiation markers, indicating that NaB treatment induces pro-differentiation effects by regulating the expression of miR-335 [ 11 ]. Although the observation that HDACis can alter miRNA expression is not new [ 13 , 14 ], and past literature indicates that both HDACis [ 15 , 16 ] and miRNAs [ 15 , 17 , 18 ] stimulate keratinocyte differentiation, in our study we report a mechanistic link between HDAC-mediated miRNA regulation and keratinocyte differentiation. These findings prompted us to investigate the possibility of targeting HDACs to address the skin barrier defect in AD.…”

Vorinostat, a histone deacetylase inhibitor, as a potential novel treatment for psoriasis

“…Given HDAC inhibitors anti‐proliferative and pro‐differentiation effects both in vitro and in vivo in various cell types including KCs, 34‐37 they may be of clinical benefit to patients affected chronic immunological (eg systemic lupus erythematosus, multiple sclerosis) and inflammatory diseases including psoriasis 38‐40 …”

“…31 HDAC inhibitors are already approved by the US Food and Drug Administration (FDA) for the treatment of refractory cutaneous T-cell lymphoma. 32,33 Given HDAC inhibitors anti-proliferative and pro-differentiation effects both in vitro and in vivo in various cell types including KCs, [34][35][36][37] they may be of clinical benefit to patients affected chronic immunological (eg systemic lupus erythematosus, multiple sclerosis) and inflammatory diseases including psoriasis [38][39][40] Vorinostat, also known as suberoylanilide hydroxamic acid or SAHA and marketed under the name of Zolinza, is a wellcharacterized HDAC inhibitor. 32,41 Besides its potential role in the management of a range of malignancies, [42][43][44] vorinostat has been shown to have a beneficial therapeutic effect in other conditions including neurological diseases, 45,46 cardiac hypertrophy, asthma and AIDS.…”