Role of Histone Deacetylases in Drug-Resistant Melanoma: Mechanisms and Therapeutic Implications
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Melanoma remains one of the most aggressive and treatment-resistant malignancies, despite advances in targeted therapies and immunotherapies. Drug resistance continues to be a major challenge, limiting long-term therapeutic success. Epigenetic regulators, particularly histone deacetylases (HDACs), play a crucial role in melanoma progression and therapy resistance by modulating gene expression, chromatin accessibility, and non-histone protein functions. HDACs influence key oncogenic pathways, including the MAPK, PI3K/AKT, and WNT/β-catenin signaling cascades, contributing to resistance against BRAF/MEK inhibitors and immune checkpoint blockade therapies. HDACs also modulate the tumor microenvironment by regulating immune cell infiltration, cytokine production, and stromal interactions, thereby promoting an immunosuppressive milieu that supports tumor survival. Given their pivotal role in drug resistance, HDAC inhibitors (HDACis) have emerged as promising therapeutic agents. HDACis induce apoptosis, suppress tumor proliferation, and enhance immune responses by reactivating tumor suppressor genes and modulating epigenetic landscapes. Preclinical and clinical studies indicate that combining HDACis with existing therapies, such as BRAF/MEK inhibitors or immune checkpoint inhibitors, can overcome resistance and improve treatment efficacy. Despite their potential, challenges remain, including toxicity, patient selection, and the identification of optimal combination strategies. Ongoing research aims to develop selective HDACis with improved efficacy and reduced adverse effects. This review comprehensively explores the role of HDACs in melanoma drug resistance, their interaction with key signaling pathways, and the therapeutic potential of HDAC inhibition. A deeper understanding of HDAC-mediated resistance mechanisms will aid in developing novel strategies to enhance melanoma treatment outcomes and overcome therapeutic resistance.