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Background: There have been significant advancements in melanoma therapies. BET inhibitors (BETis) show promise in impairing melanoma growth. However, identifying BETi-sensitive melanoma subtypes is challenging. Methods and Results: We analyzed 48 melanoma cell lines and 104 patients and identified two acetylation-immune subtypes (ALISs) in the cell lines and three ALISs in the patients. ALIS I, with high <i>HAT1</i> and low <i>KAT2A</i> expression, showed a higher sensitivity to the BETi JQ-1 than ALIS II. ALIS III had low <i>HAT1</i> expression. The TAD2B expression was low in ALIS I and II. <i>KAT2A</i> and <i>HAT1</i> expressions were negatively correlated with the methylation levels of their CG sites (<i>p</i> = 0.0004 and 0.0003). Immunological gene sets, including B cell metagenes, activated stroma-related genes, fibroblast TGF response signatures (TBRS), and T cell TBRS-related genes, were up-regulated in ALIS I. Furthermore, <i>KAT2A</i> played a key role in regulating BETi sensitivity. Conclusions: The sensitivity of ALIS I to the BETi JQ-1 may be due to the inhibition of BETi resistance pathways and genes by low <i>KAT2A</i> expression and the dysregulation of the immune microenvironment by high <i>HAT1</i> expression resulting from the absence of immune cells. ALIS I had the worst progression but showed sensitivity to BETi and B-cell-related immunotherapy, despite not responding to BRAF inhibitors.