MITF (microphthalmia-associated transcription factor) represents a melanocytic lineage-specific transcription factor whose role is profoundly extended in malignant melanoma. Over the last few years, the function of MITF has been tightly connected to plasticity of melanoma cells. MITF participates in executing diverse melanoma phenotypes defined by distinct gene expression profiles. Mutation-dependent alterations in MITF expression and activity have been found in a relatively small subset of melanomas. MITF activity is rather modulated by its upstream activators and suppressors operating on transcriptional, post-transcriptional and post-translational levels. These regulatory mechanisms also include epigenetic and microenvironmental signals. Several transcription factors and signaling pathways involved in the regulation of MITF expression and/or activity such as the Wnt/β-catenin pathway are broadly utilized by various types of tumors, whereas others, e.g., BRAF^V600E/ERK1/2 are more specific for melanoma. Furthermore, the MITF activity can be affected by the availability of transcriptional co-partners that are often redirected by MITF from their own canonical signaling pathways. In this review, we discuss the complexity of a multilevel regulation of MITF expression and activity that underlies distinct context-related phenotypes of melanoma and might explain diverse responses of melanoma patients to currently used therapeutics.

The BCL-2 family of proteins integrates signals that trigger either cell survival or apoptosis. The balance between pro-survival and pro-apoptotic proteins is important for tissue development and homeostasis, while impaired apoptosis contributes to several pathologies and can be a barrier against effective treatment. BCL-w is an anti-apoptotic protein that shares a sequence similarity with BCL-X_L, and exhibits a high conformational flexibility. BCL-w level is controlled by a number of signaling pathways, and the repertoire of transcriptional regulators largely depends on the cellular and developmental context. As only a few disease-relevant genetic alterations of BCL2L2 have been identified, increased levels of BCL-w might be a consequence of abnormal activation of signaling cascades involved in the regulation of BCL-w expression. In addition, BCL-w transcript is a target of a plethora of miRNAs. Besides its originally recognized pro-survival function during spermatogenesis, BCL-w has been envisaged in different types of normal and diseased cells as an anti-apoptotic protein. BCL-w contributes to survival of senescent and drug-resistant cells. Its non-apoptotic role in the promotion of cell migration and invasion has also been elucidated. Growing evidence indicates that a high BCL-w level can be therapeutically relevant in neurodegenerative disorders, neuron dysfunctions and after small intestinal resection, whereas BCL-w inhibition can be beneficial for cancer patients. Although several drugs and natural compounds can bi-directionally affect BCL-w level, agents that selectively target BCL-w are not yet available. This review discusses current knowledge on the role of BCL-w in health, non-cancerous diseases and cancer.

HSP90 (heat shock protein 90) is an ATP-dependent molecular chaperone involved in a proper folding and maturation of hundreds of proteins. HSP90 is abundantly expressed in cancer, including melanoma. HSP90 client proteins are the key oncoproteins of several signaling pathways controlling melanoma development, progression and response to therapy. A number of natural and synthetic compounds of different chemical structures and binding sites within HSP90 have been identified as selective HSP90 inhibitors. The majority of HSP90-targeting agents affect N-terminal ATPase activity of HSP90. In contrast to N-terminal inhibitors, agents interacting with the middle and C-terminal domains of HSP90 do not induce HSP70-dependent cytoprotective response. Several inhibitors of HSP90 were tested against melanoma in pre-clinical studies and clinical trials, providing evidence that these agents can be considered either as single or complementary therapeutic strategy. This review summarizes current knowledge on the role of HSP90 protein in cancer with focus on melanoma, and provides an overview of structurally different HSP90 inhibitors that are considered as potential therapeutics for melanoma treatment.

Interferon-gamma (IFN-γ) is a cytokine produced mainly by immune cells and can affect cancer cells by modulating the activity of multiple signaling pathways, including the canonical Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) cascade. In melanoma, IFN-γ can exert both anticancer effects associated with cell-cycle arrest and cell death induction and protumorigenic activity related to immune evasion leading to melanoma progression. Notably, IFN-γ plays a crucial role in the response of melanoma patients to immunotherapy with immune checkpoint inhibitors (ICIs), which are currently used in the clinic. As these agents target programmed death-1 (PD-1) and its ligand (PD-L1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) and lymphocyte-activation gene 3 (LAG-3), they are designed to restore the antimelanoma immune response. In this respect, IFN-γ produced by cells in the tumor microenvironment in response to ICIs has a beneficial influence on both immune and melanoma cells by increasing antigen presentation, recruiting additional T-cells to the tumor site, and inducing direct antiproliferative effects and apoptosis in melanoma cells. Therefore, IFN-γ itself and IFN-γ-related gene signatures during the response to ICIs can constitute biomarkers or predictors of the clinical outcome of melanoma patients treated with ICIs. However, owing to its multifaceted roles, IFN-γ can also contribute to developing mechanisms associated with the acquisition of resistance to ICIs. These mechanisms can be associated with either decreased IFN-γ levels in the tumor microenvironment or diminished responsiveness to IFN-γ due to changes in the melanoma phenotypes associated with affected activity of other signaling pathways or genetic alterations e.g., in JAK, which restricts the ability of melanoma cells to respond to IFN-γ. In this respect, the influence of IFN-γ on melanoma-specific regulators of the dynamic plasticity of the cell phenotype, including microphthalmia-associated transcription factor (MITF) and nerve growth factor receptor (NGFR)/CD271 can affect the clinical efficacy of ICIs. This review comprehensively discusses the role of IFN-γ in the response of melanoma patients to ICIs with respect to its positive influence and role in IFN-γ-related mechanisms of resistance to ICIs as well as the potential use of predictive markers on the basis of IFN-γ levels and signatures of IFN-γ-dependent genes.