Abstract
While non-melanoma skin cancers (NMSCs) are the most common tumours in humans, only the sub-type cutaneous squamous cell carcinoma (cSCC), might become metastatic with high lethality. We have recently identified a regulatory pathway involving the lncRNA transcript uc.291 in controlling the expression of epidermal differentiation complex genes via the interaction with ACTL6A, a component of the chromatin remodelling complex SWI/SNF. Since transcribed ultra-conserved regions (T-UCRs) are expressed in normal tissues and are deregulated in tumorigenesis, here we hypothesize a potential role for dysregulation of this axis in cSCC, accounting for the de-differentiation process observed in aggressive poorly differentiated cutaneous carcinomas. We therefore analysed their expression patterns in human tumour biopsies at mRNA and protein levels. The results suggest that by altering chromatin accessibility of the epidermal differentiation complex genes, down-regulation of uc.291 and BRG1 expression contribute to the de-differentiation process seen in keratinocyte malignancy. This provides future direction for the identification of clinical biomarkers in cutaneous SCC. Analysis of publicly available data sets indicates that the above may also be a general feature for SCCs of different origins.
Highlights
The epidermis is a pluri-stratified and keratinized epithelium comprising a proliferative compartment and a multi-stage differentiation compartment
BRG1 expression was strongly downregulated in both BCCs and cutaneous squamous cell carcinoma (cSCC), ACTL6A expression was unchanged or tended to increase (Fig. 1b)
It has been shown that BRG1, the catalytic subunit of the SWI/SNF complex, binds to many regions within the keratinocytes epidermal differentiation complex (EDC) locus to control local remodelling of the chromatin fibre within the EDC at the nucleosome level in an ATP-dependent manner [49,50,51,52]
Summary
The epidermis is a pluri-stratified and keratinized epithelium comprising a proliferative compartment (basal layer) and a multi-stage differentiation compartment (spinous, granular and corneous layers). The epidermis gives rise to two common cancer-types derived by the proliferating keratinocytes (basal cell carcinoma, BCC) and differentiating keratinocytes (cutaneous squamous cell carcinoma, cSCC). BCC, the most common type of NMSC, accounts for almost 90% of all skin cancers [1] and originates from the interfollicular epidermis stem cells, the hair follicle infundibulum cells or the hair follicle bulge cells [2,3,4]. CSCCs is the second most frequent type of skin malignancy [7]. It usually arises from the in situ lesions named actinic keratosis, or it may grow in photo-exposed areas as de novo lesion [7]. It usually arises from the in situ lesions named actinic keratosis, or it may grow in photo-exposed areas as de novo lesion [7]. cSCCs
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