Unraveling the role of hypoxia-inducible factors in cutaneous melanoma: from mechanisms to therapeutic opportunities

Abstract

Hypoxia is a common feature of solid malignancies, including cutaneous melanoma (CM). Hypoxia-inducible factor (HIF)-1α and HIF-2α orchestrate cellular responses to hypoxia and coordinate a transcriptional program that promote several aggressive features in CM, such as angiogenesis, epithelial-mesenchymal transition, metastasis formation, metabolic rewiring, and immune escape. BRAF^V600E, which is the most frequent mutation observed in CM patients, usually increases HIF-α signaling not only in hypoxia, but also in normoxic CM cells, enabling HIF-1α and HIF-2α to continuously activate downstream molecular pathways. In this review, we aim to provide a comprehensive overview of the intricate role and regulation of HIF-1α and HIF-2α in CM, with a brief focus on the complex interactions between HIF-α subunits and non-coding RNAs. We also discuss HIF-α-mediated cellular responses in normoxia along with the mechanisms that allow HIF-α subunits to maintain their stability under normal oxygen conditions. Finally, we resume available evidence on potential therapeutic approaches aimed at targeting HIF-1α and/or HIF-2α.

Keywords: Cutaneous melanoma; Hypoxia; Hypoxia-inducible factors; Non-coding RNAs; Normoxia.

Fig. 1

Schematic illustration of HIF-1α, HIF-2α, HIF-3α isoforms and HIF-1β protein. As shown, HIF-α proteins possess a bHLH and two PAS domains, responsible for the heterodimerization. Instead of having the C-TAD domain, HIF-3α has a LZIP domain that allows the protein interaction. The constitutively expressed HIF-1β does not contain the ODD, N-TAD and ID domains. Abbreviations are listed in the legend section. Created in BioRender (https://BioRender.com/s38c417)

Fig. 2

Overview of the multiple pathways impacting on HIF-1α in CM. In the upper panel, a graphic representation of the main pathways regulated by HIF-1α under hypoxic conditions (1 kPa O₂ levels) in CM is shown. Conversely, the lower panel resumes pathways that are controlled by HIF-1α in normoxia (18 kPa O₂ levels). Panels are divided into pro-tumorigenic (blue) and anti-tumorigenic (orange). Created in BioRender (https://BioRender.com/p73u915). Abbreviations: HIF: Hypoxia-inducible factor; ROS: Reactive oxygen species; PARP1: Poly (ADP-ribose) polymerase; PAR: Poly ADP-ribose; HDAC8: Histone deacetylase 8; IL-18R: interleukin-18 receptor; RAC1: Rac Family Small GTPase 1; NF-kB: The Nuclear Factor Kappa B; VEGF: Vascular endothelial growth factor; ER: endoplasmic reticulum; NLGN4X: Neuroligin; VBP1: VHL Binding Protein 1; VHL: Von Hippel-Lindau; DRD2: D2 dopamine receptor; GPR81: G protein-coupled receptor 81; PKA: protein kinase A; TEV: tumour-derived extracellular vesicles; SOX2: SRY-box transcription factor; TCA: Tricarboxylic acid; GPX3: Glutathione Peroxidase 3; NOX5: NADPH oxidase 5; EMT: Epithelial to mesenchymal transition; BNIP3: BCL-2 interacting protein 3; NCOA4: Nuclear Receptor Coactivator 4; MITF: Microphthalmia-associated transcription factor; ANXA3: Annexin A3; PDK1: Pyruvate dehydrogenase kinase; UPR: unfolded protein response

Fig. 3

Schematic representation of non-coding RNAs involved in HIF-1α pathway regulation in CM. In the upper semicircle, a summary of the current advances about the bidirectional interactions between HIF-1α and miRNAs in CM (blue: suppressor miRNAs; orange: oncogenic miRNAs). The lower semicircle illustrates a graphic representation of the mechanism by which the lncRNA linc00518 modulates HIF-1α expression in CM. Created in BioRender (https://BioRender.com/833o824). Abbreviations: HIF: Hypoxia-inducible factor; miR: mirna; CM: cutaneous melanoma; ROS: Reactive oxygen species; MNT: MAX Network Transcriptional Repressor; CTL: cytotoxic T lymphocyte; TCA: Tricarboxylic acid; PDK4: Pyruvate Dehydrogenase Kinase 4; LDHA: Lactate dehydrogenase A; PTPN1:Protein Tyrosine Phosphatase Non-Receptor Type 1; HOXA1: Homeobox A1; TP53I11. Tumor Protein P53 Inducible Protein 11.LDHA: Lactate dehydrogenase A; PTPN1:Protein Tyrosine Phosphatase Non-Receptor Type 1; HOXA1: Homeobox A1; TP53I11. Tumor Protein P53 Inducible Protein 11