EZH2 in Acral Lentiginous Melanoma: Molecular, Epigenetic, and Therapeutic Perspectives

Acral lentiginous melanoma (ALM) is characterized by a low mutational burden, frequent chromosomal rearrangements, and profound epigenetic dysregulation, distinguishing it from ultraviolet (UV)-induced melanoma. Among the epigenetic regulators, Enhancer of Zeste Homolog 2 (EZH2), the catalytic component of the Polycomb Repressive Complex 2 (PRC2), plays a central role in chromatin compaction and transcriptional repression through trimethylation of histone H3 on lysine 27 (H3K27me3). EZH2 overexpression or hyperactivation contributes to tumor progression, immune evasion, and therapeutic resistance. Recent multi-omic studies have highlighted the importance of EZH2 in regulating melanoma plasticity, immune modulation, and metabolic reprogramming. In ALM, where canonical oncogenic mutations such as BRAF V600E and NRAS Q61 are less frequent, EZH2-driven epigenetic mechanisms may play an even more dominant role in tumor initiation and progression. Pharmacological inhibitors of EZH2, including tazemetostat, have shown promise in preclinical melanoma models by restoring antigen presentation, enhancing CD8⁺ T-cell infiltration, and reversing transcriptional programs associated with immune resistance. This review aims to summarize the role of EZH2 in the molecular pathogenesis of ALM, emphasizing its contributions to epigenetic regulation, tumor plasticity, and immune escape, and discusses emerging therapeutic strategies targeting EZH2-mediated pathways to improve outcomes for this aggressive melanoma subtype.