Ali Ahlam, Zhang Fengyu, Maguire Aaron, Byrne Tara, Weiner-Gorzel Karolina, Bridgett Stephen, O'Toole Sharon, O'Leary John, Beggan Caitlin, Fitzpatrick Patricia, McCann Amanda, Furlong Fiona
Patrick G Johnston Centre for Cancer Research, Queen's University, Belfast BT97BL, UK.
School of Pharmacy, Queen's University, Belfast BT97BL, UK.
Cancers (Basel). 2020 Dec 11;12(12):3734. doi: 10.3390/cancers12123734.
Histone deacetylase 6 (HDAC6) is a unique histone deacetylating enzyme that resides in the cell cytoplasm and is linked to the modulation of several key cancer related responses, including cell proliferation and migration. The promising anti-cancer response of the first-generation HDAC6 catalytic inhibitors continues to be assessed in clinical trials, although its role in high grade serous ovarian cancer is unclear. This study investigated HDAC6 tumor expression by immunohistochemistry in high-grade serous ovarian cancer (HGSOC) tissue samples and a meta-analysis of HDAC6 gene expression in ovarian cancer from publicly available data. The pharmacological activity of HDAC6 inhibition was assessed in a patient-derived model of HGSOC. HDAC6 was found to be highly expressed in HGSOC tissue samples and in the patient-derived HGSOC cell lines where higher HDAC6 protein and gene expression was associated with a decreased risk of death (hazard ratio (HR) 0.38, (95% confidence interval (CI), 0.16-0.88; = 0.02); HR = 0.88 (95% CI, 0.78-0.99; = 0.04)). Similarly, the multivariate analysis of HDAC6 protein expression, adjusting for stage, grade, and cytoreduction/cytoreductive surgery was associated with a decreased risk of death (HR = 0.19 (95% CI, 0.06-0.55); = 0.002). Knock-down of HDAC6 gene expression with siRNA and protein expression with a HDAC6 targeting protein degrader decreased HGSOC cell proliferation, migration, and viability. Conversely, the selective inhibition of HDAC6 with the catalytic domain inhibitor, Ricolinostat (ACY-1215), inhibited HDAC6 deacetylation of α-tubulin, resulting in a sustained accumulation of acetylated α-tubulin up to 24 h in HGSOC cells, did not produce a robust inhibition of HDAC6 protein function. Inhibition of HGSOC cell proliferation by ACY-1215 was only achieved with significantly higher and non-selective doses of ACY-1215. In summary, we demonstrated, for the first time, that HDAC6 over-expression in HGSOC and all ovarian cancers is a favorable prognostic marker. We provide evidence to suggest that inhibition of HDAC6 catalytic activity with first generation HDAC6 inhibitors has limited efficacy as a monotherapy in HGSOC.
组蛋白去乙酰化酶6（HDAC6）是一种独特的组蛋白去乙酰化酶，存在于细胞质中，与多种关键的癌症相关反应的调节有关，包括细胞增殖和迁移。第一代HDAC6催化抑制剂有前景的抗癌反应仍在临床试验中进行评估，尽管其在高级别浆液性卵巢癌中的作用尚不清楚。本研究通过免疫组织化学方法研究了高级别浆液性卵巢癌（HGSOC）组织样本中HDAC6的肿瘤表达情况，并对公开数据中卵巢癌的HDAC6基因表达进行了荟萃分析。在一个源自患者的HGSOC模型中评估了HDAC6抑制的药理活性。发现HDAC6在HGSOC组织样本和源自患者的HGSOC细胞系中高表达，其中较高的HDAC6蛋白和基因表达与死亡风险降低相关（风险比（HR）0.38，（95%置信区间（CI），0.16 - 0.88；P = 0.02）；HR = 0.88（95%CI，0.78 - 0.99；P = 0.04））。同样，对HDAC6蛋白表达进行多因素分析，校正分期、分级和细胞减灭术/细胞减灭性手术后，与死亡风险降低相关（HR = 0.19（95%CI，0.06 - 0.55）；P = 0.002）。用小干扰RNA敲低HDAC6基因表达以及用靶向HDAC6的蛋白降解剂降低蛋白表达，可降低HGSOC细胞的增殖、迁移和活力。相反，用催化结构域抑制剂瑞可利司他（ACY - 1215）选择性抑制HDAC6，可抑制HDAC6对α - 微管蛋白的去乙酰化作用，导致HGSOC细胞中乙酰化α - 微管蛋白持续积累长达24小时，但并未对HDAC6蛋白功能产生强大的抑制作用。只有使用显著更高且非选择性的ACY - 1215剂量才能实现其对HGSOC细胞增殖的抑制。总之，我们首次证明，HDAC6在HGSOC和所有卵巢癌中的过表达是一个良好的预后标志物。我们提供的证据表明，第一代HDAC6抑制剂抑制HDAC6催化活性作为HGSOC的单一疗法疗效有限。
