A Novel Acetylation-Immune Subtyping for the Identification of a BET Inhibitor-Sensitive Subgroup in Melanoma

SIMPLE SUMMARY: BET inhibitors (BETis) are a class of promising therapies that inhibit the growth of melanoma cells. However, how to identify BETi-sensitive subtypes of melanoma is still unclear. We analyzed 48 melanoma cell lines and 104 melanoma patients and identified two acetylation-immune subtypes (ALISs) in the cell lines and three ALISs in the patients. The ALIS I cell lines showed a higher sensitivity to the BET inhibitor JQ-1, while the ALIS I patients had the poorest survival outcomes. We also compared immune-related gene sets and key mRNAs associated with histone acetylation and JQ-1 sensitivity among the three ALISs. The results indicated that the sensitivity of the ALIS I cell lines to JQ-1 might be attributable to the impact of the low expression of KAT2A and the high expression of HAT1 on the immune microenvironment. The ALIS I patients demonstrated sensitivity to BET inhibitors and B-cell-related immunotherapy, but did not respond to BRAF inhibitors. ABSTRACT: 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 HAT1 and low KAT2A expression, showed a higher sensitivity to the BETi JQ-1 than ALIS II. ALIS III had low HAT1 expression. The TAD2B expression was low in ALIS I and II. KAT2A and HAT1 expressions were negatively correlated with the methylation levels of their CG sites (p = 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, KAT2A 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 KAT2A expression and the dysregulation of the immune microenvironment by high HAT1 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.