Prior studies have shown that combinations of histone deacetylase (HDAC) and BRAF inhibitors (BRAFi) have synergistic effects on BRAFi-resistant melanoma through enhanced apoptosis and inhibition of the cAMP-dependent drug resistance pathway. However, little is known about the expression of various HDACs and their associations with BRAF/NRAS mutation status, clinicopathologic characteristics, and patient outcome. The present study extensively profiled HDAC class 1 and their targets/regulators utilizing immunohistochemistry in human melanoma samples from patients with stage IV melanoma, known BRAF/NRAS mutational status, and detailed clinicopatholgical data. HDAC8 was increased in BRAF-mutated melanoma (P=0.016), however, no association between expression of other HDACs and NRAS/BRAF status was identified. There was also a correlation between HDAC1, HDAC8 expression, and phosphorylated NFκb p65 immunoreactivity (P<0.001). Increased cytoplasmic HDAC8 immunoreactivity was independently associated with an improved survival from both diagnosis of primary melanoma and from first detection of stage IV disease to melanoma death on multivariate analysis (HR 0.992, 95% CI 0.987-0.996; P<0.001 and HR 0.993, 95% CI 0.988-0.998; P=0.009, respectively). These results suggest not only that HDAC8 may be a prognostic biomarker in melanoma, but also provide important data regarding the regulation of HDACs in melanoma and a rational basis for targeting them therapeutically.
本研究收集IV期、已知BRAF/NRAS突变状态并有详细临床病理资料的黑色素瘤标本，用免疫组化方法详细研究1类HDAC及其下游目标因子/上游调节因子表达。BRAF突变黑色素瘤HDAC8表达增加（P = 0.016），但是，未发现其他HDACs表达和NRAS/BRAF基因状态的相关性。HDAC1、HDAC8表达和磷酸化NFκb p65免疫表达亦相关（P＜0.001）。多变量分析显示，从诊断原发性黑色素瘤算起、或从首次诊断IV期疾病算起到死亡，胞浆HDAC8免疫表达都与生存改善独立相关（分别为HR 0.992，95% CI 0.987-0.996；P＜0.001；HR 0.993，95% CI 0.988-0.998；P = 0.009）。