Department of Pathology, Saitama Medical University International Medical Centre, Saitama, Japan.
Departments of Obstetrics and Gynaecology, Oita University Faculty of Medicine, Oita, Japan.
Sci Rep. 2019 Feb 20;9(1):2397. doi: 10.1038/s41598-019-38653-0.
Ovarian clear cell carcinoma (OCCC) is associated with a frequent loss in ARID1A function. ARID1A reportedly suppresses histone deacetylase (HDAC)6 in OCCC directly. Here, we evaluated the clinical significance of HDAC6 expression and its related factors in terms of ARID1A status. Immunohistochemical expression of HDAC6, hypoxia inducible factors-1α (HIF-1α), programmed death-1 ligand (PD-L1), CD44 (cancer stem cell marker), and ARID1A was analysed for 106 OCCC patients. High nuclear HDAC6 expression correlated with patient death (p = 0.038). In the multivariate analysis of overall survival, surgical status (complete or incomplete resection) (hazard ratio (HR) = 17.5; p = <0.001), HDAC6 nuclear expression (HR = 1.68; p = 0.034), and PD-L1 expression (HR = 1.95; p = 0.022) were the independent prognostic factors. HDAC6 upregulation and ARID1A loss did not necessarily occur simultaneously. High HDAC6 expression was associated with poor prognosis in OCCC with ARID1A loss; this was not observed without ARID1A loss. HDAC6 expression showed a significant positive correlation with HIF-1α, PD-L1, and CD44. In OCCC, HDAC6 involvement in prognosis depended on ARID1A status. HDAC6 also led to immuno- and hypoxia- tolerance and cancer stem cell phenotype. HDAC6 is a promising therapeutic target for OCCC with loss of ARID1A.
卵巢透明细胞癌（OCCC）与 ARID1A 功能的频繁丧失有关。据报道，ARID1A 直接抑制 OCCC 中的组蛋白去乙酰化酶（HDAC）6。在这里，我们根据 ARID1A 状态评估了 HDAC6 表达及其相关因素的临床意义。对 106 例 OCCC 患者的 HDAC6、缺氧诱导因子-1α（HIF-1α）、程序性死亡配体-1（PD-L1）、CD44（癌症干细胞标志物）和 ARID1A 的免疫组织化学表达进行了分析。高核 HDAC6 表达与患者死亡相关（p=0.038）。在总生存的多变量分析中，手术状态（完全或不完全切除）（危险比（HR）=17.5；p<0.001）、HDAC6 核表达（HR=1.68；p=0.034）和 PD-L1 表达（HR=1.95；p=0.022）是独立的预后因素。HDAC6 的上调和 ARID1A 的缺失不一定同时发生。在 ARID1A 缺失的情况下，高 HDAC6 表达与 OCCC 的不良预后相关；而在 ARID1A 缺失的情况下则没有观察到这种相关性。HDAC6 表达与 HIF-1α、PD-L1 和 CD44 呈显著正相关。在 OCCC 中，HDAC6 对预后的影响取决于 ARID1A 状态。HDAC6 还导致免疫和缺氧耐受以及癌症干细胞表型。HDAC6 是治疗 ARID1A 缺失的 OCCC 的一个有前途的靶点。
