Putative role of HIF transcriptional activity in melanocytes and melanoma biology

Abstract

Hypoxia-inducible factor-1α (HIF-1α) is a highly oxygen sensitive bHLH protein that is part of the heterodimeric HIF-1 transcription factor. Under hypoxic stress, HIF-1 activity is induced to control expression of multiple downstream target genes, including vascular endothelial growth factor (VEGF). The normal epidermis exists in a constant mild hypoxic microenvironment and constitutively expresses HIF-1α and HIF-2α. Expression of HIF-1α and/or HIF-2α has been suggested to correlate with the increased malignant potential of melanocytes, therefore, failures of melanoma therapies may be partially linked to high HIF activity. Notably, melanomas that have the V600E BRAF mutation exhibit increased HIF-1α expression. We have utilized a bioinformatics approach to identify putative hypoxia response elements (HREs) in a set of genes known to participate in the process of melanogenesis (includingTRPM1, SLC45A2, HRAS, C-KIT, PMEL and CRH). While some of the mechanistic links between these genes and the HIF pathway have been previously explored, others await further investigation. Although agents targeting HIF activity have been proposed as novel treatment modalities for melanoma, there are currently no clinical trials in progress to test their efficacy in melanoma.

The role of melanogenesis in regulation of melanoma behavior: Melanogenesis leads to stimulation of HIF-1α expression and HIF-dependent attendant pathways

“…However, a significant correlation was observed between progression and HIF-1α expression in highly advanced melanomas, with higher HIF-1α levels in thicker (≥pT2) but not thin (pT1) melanomas in comparison to melanocytic nevi. A similar trend was reported previously by other investigators [56]. Despite the limitations listed above, our pathologic data support the hypothesis that overexpression of HIF-1α can contribute to the increased aggressiveness of melanoma, which is in agreement to prior reports in the literature on melanomas [100, 102, 103] and other tumor types [38, 44].…”

“…Multiple putative HREs were also identified for DHCR7 : five HRE sites were identified within the first 1000 bp of the transcriptional start site (TSS; p <0.05 to p <0.001). Additional HPA axis genes, including PCKS1 , PCSK2 , MC2 , and the previously identified POMC and MC1 each contained at least two putative HREs within the regulatory regions [56]. In agreement with this analysis, we discovered that expression of these genes is also stimulated by melanogenesis, as shown in Table 7, which suggests involvement of HIF-1α.…”

“…In the skin, UVB exposure will transform 7DHC to vitamin D3 [94], which can be further hydroxylated by CYP27A1 and CYP27B1 [95] to its active form, 1,25-dihydroxyvitamin D3 (calcitriol). Of note, both of these CYP genes were previously shown to contain putative HRE elements [56]. …”

“…In the context of above studies and the literature on the constitutive expression of HIF-1α in melanomas [56, 98-100], we have evaluated a relationship between HIF-1α expression and the progression of melanocytic lesions in a large panel of pigmented lesions obtained from patients listed in Table 2. Representative immunostaining of HIF-1α in melanocytic nevi and melanomas is shown in Fig 5.…”

“…Some of the classic HIF target genes include multiple enzymes in the glycolytic pathway, such as lactate dehydrogenase A (LDH-A), pyruvate dehydrogenase kinase, isozyme 1 (PDK1), aldolase A, fructose-bisphosphate (ALDOA), hexokinase 2 (HK2), BNIP3 (BCL2/adenovirus E1B 19kDa interacting protein 3), sodium hydrogen exchanger (NHEI), monocarboxylate transporter 4 (MCT4), glucose transporters 1 and 4 (GLUT-1 and GLUT-4) and angiogenic factors, including vascular endothelial growth factor A (VEGF), growth factors and transferrin receptor 1 [38, 50-54]. HIF-1α is over-expressed in several types of human cancers, including melanoma [55, 56] and direct impacts several hallmarks of malignancy [39]. …”