Hormonal, stem cell and Notch signalling as possible mechanisms of disease in hidradenitis suppurativa: a systems‐level transcriptomic analysis

Dear Editor, Hidradenitis suppurativa (HS) is a chronic skin disease marked by abscesses, sinus tract formation and profound scarring. Although the inflammatory nature of HS is well described, its aetiology remains elusive. Deciphering the molecular pathogenesis of HS will facilitate development of new therapeutics for this debilitating disease. Using publicly available microarray data, this exploratory work identifies differentially regulated biological pathways in HS. Blok et al., who submitted this microarray to the National Center for Biotechnology Information (NCBI) have previously identified a proinflammatory response as the prime dysregulated pathway in HS.1 In further analysis, the present work uncovers evidence that HS lesions have increased androgen receptor (AR) transcriptional activity, activation of stem cell‐associated transcriptional pathways and upregulation of Notch‐associated genetic loci. Gene expression microarray data derived from skin biopsies of 17 patients with HS and 13 patient‐matched control biopsies were downloaded from NCBI‐GEO (GSE72702) and analysed using BRB‐ArrayTools, DAVID and Enrichr.1 2 Differentially expressed genes (DEGs) between HS and normal skin were subjected to multiple bioinformatic analyses focusing on transcriptional, positional and pathway‐enrichment readouts. This bioinformatic study involved no human subject intervention, thus Institutional Review Board approval was waived by Midwestern University. Genes upregulated in HS lesions were analysed to determine if they share common transcription factor (TF) binding sites. Results demonstrate enrichment for genes regulated by AR, as well as TFs associated with epidermal stem cells – NANOG, TP63 and vitamin D receptor (VDR) (Fig. 1a). DEGs were also analysed to identify gene sets sharing common chromosomal position. Results reveal enrichment for a set of 22 genes that reside on chromosomal cytoband 1q21–1q25 (Fig. 1b), a previously identified causative genetic locus in familial HS that is linked to Notch signalling.3 Many of these genes belong to the epidermal differentiation complex, which resides in cytoband 1q21. Indeed, when subjected to functional pathway analysis, these 22 genes demonstrate enrichment for keratinocyte differentiation and epidermis development pathways. Enrichment analysis of genes upregulated in hidradenitis suppurativa (HS) lesional vs. nonlesional skin. (a) Genes upregulated twofold or higher in HS lesional skin vs. nonlesional skin analysed in Enrichr to identify regulation by transcription factors according to ENCODE and ChEA consensus transcription factors from ChIP‐X. Genes under the transcriptional control of vitamin D receptor (VDR), NANOG, androgen receptor (AR) and TP63 are significantly enriched in HS lesional skin. Enrichment results are presented as combined score ranks for transcription factor binding‐site enrichment, which are derived from P‐values and z‐scores. Red bars signify significantly enriched results with q ≤ 0·05, where the q‐value is an adjusted P‐value using the Benjamini–Hochberg correction for multiple hypothesis testing. (b) List of 22 genes significantly upregulated in HS lesional skin vs. nonlesional skin that reside on cytobands 1q21–24. The present study provides novel evidence of increased AR transcriptional activity in HS, which aligns with known hormonal risk factors for the disease.4 Although there is conflicting evidence for the role of hormones in HS pathogenesis, previous studies have focused on hormone concentrations, steroid receptor protein expression or enzyme activity in tissues – none of which necessarily correlate to hormone receptor‐coupled gene transcription.4 This work also identifies increased expression of genes regulated by three key stem cell TFs: NANOG, p63 and VDR. NANOG is a TF that regulates pluripotency in embryonic stem cells and is thought to be important in many adult stem cells.5 A marker of basal epithelial cells in many tissues, p63 is also a critically important TF in epidermal stem cells.5 Finally, VDR signalling has more recently been implicated as a regulator of proliferation and differentiation in multiple tissue stem cells, including hematopoietic, mesenchymal and epidermal tissues.6 Linking these findings is the fact that epidermal stem cells are known to reside within the bulge of the pilosebaceous unit (PSU), which is an androgen‐regulated structure. Indeed, many adult tissue stem cells are regulated by hormones, including in breast, prostate and hematopoietic tissues.6 Thus, the present work links hormonal and stem‐cell transcriptional activity to known epidemiological risk factors and histological characteristics of HS. The identification of increased gene expression from cytoband 1q21–1q25, a previously identified genetic locus in familial HS, is intriguing in multiple respects.3 Genes in this cytoband are known members of the γ‐secretase–Notch signalling pathway and are involved in epidermal development and keratinocyte differentiation pathways. Others have noted that altered Notch signalling might induce an inflammatory state.7 Interestingly, despite data demonstrating that γ‐secretase complex genes are the most commonly mutated genes in both familial and sporadic cases of HS, a recent systematic review found little evidence that these mutations result in measurable changes in downstream Notch signalling.3 However, if γ‐secretase–Notch signalling were primarily altered in a rare population of epidermal stem cells, the protein level and functional studies assessed in this review may not have faithfully recapitulated signalling events in the stem‐cell niche. Finally, circumstantial evidence from the prostate and breast literature suggests that AR signalling impinges on and modulates Notch signalling.8 A hypothetical model of disease is thus proposed whereby hormonal dysregulation of epidermal stem cells within the PSU can give rise to defects in keratinocyte proliferation and differentiation, resulting in the characteristic sequelae of HS: hyperproliferation, hyperkeratinization, plugging and inflammation. These findings warrant further studies into the hormonal basis of HS and whether such signalling might alter stem‐cell homeostasis in HS pathogenesis. A clearer understanding of the underlying mechanisms of disease in HS may thus help advance clinical trials of relevant drugs, particularly androgen‐blockade therapies. The author is indebted to Joerg Albrecht MD and Gail S. Prins PhD for their critical review of this manuscript. Funding sources: no external funding. Conflicts of interest: none to declare.