Islam Muhtadi M, Banerjee Tapahsama, Packard Colin Z, Kotian Shweta, Selvendiran Karuppaiyah, Cohn David E, Parvin Jeffrey D
Department of Biomedical Informatics, The Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, United States.
Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210, United States.
Gynecol Oncol. 2017 Mar;144(3):613-620. doi: 10.1016/j.ygyno.2017.01.009. Epub 2017 Jan 7.
We analyzed histone deacetylase 10 (HDAC10) for function in the context of the DNA damage response in BRCA1-null ovarian cancer cells as well as evaluated the potential of general HDAC inhibitors in primary ovarian carcinoma cells. HDAC10 had previously been shown to be highly stimulatory to the process of homology directed repair in HeLa cells, and in this study we investigated whether HDAC10 could impact in vitro the response to anticancer therapies. We hypothesized that the loss of HDAC10 would sensitize cells to platinum therapy.
We combined informatics analysis of large DNA sequencing datasets from ovarian cancer tumors with tissue culture based assays of primary and established cell lines to test for sensitivity to platinum therapy if HDAC10 activity was inhibited or depleted.
Using The Cancer Genome Atlas (TCGA) dataset, we found that deep deletions in HDAC10 occurred in 5-10% of ovarian cancer tumors. From the TCGA data we found that low HDAC10 mRNA levels correlated with platinum sensitivity of the tumors. Cell proliferation and DNA damage assays in a BRCA1-null ovarian carcinoma cell line demonstrated reduced DNA repair capacity and sensitization of platinum therapy. Similarly, primary ovarian carcinoma cells demonstrated a sensitization to platinum therapies when treated with HDAC inhibitors.
From the results of this study, we suggest that the inhibition of HDAC10 may potentiate the effects of platinum therapies in ovarian tumors.
我们分析了组蛋白去乙酰化酶10（HDAC10）在BRCA1基因缺失的卵巢癌细胞DNA损伤反应中的功能，并评估了通用HDAC抑制剂对原发性卵巢癌细胞的作用。此前研究表明HDAC10对HeLa细胞的同源定向修复过程具有高度促进作用，在本研究中，我们调查了HDAC10是否会在体外影响对抗癌疗法的反应。我们假设HDAC10的缺失会使细胞对铂类疗法敏感。
我们将来自卵巢癌肿瘤的大型DNA测序数据集的信息学分析与基于组织培养的原代细胞系和已建立细胞系的检测相结合，以测试如果HDAC10活性被抑制或耗尽时对铂类疗法的敏感性。
使用癌症基因组图谱（TCGA）数据集，我们发现5%-10%的卵巢癌肿瘤中存在HDAC10的深度缺失。从TCGA数据中我们发现低HDAC10 mRNA水平与肿瘤的铂敏感性相关。在BRCA1基因缺失的卵巢癌细胞系中进行的细胞增殖和DNA损伤检测表明DNA修复能力降低以及对铂类疗法敏感。同样，原发性卵巢癌细胞在用HDAC抑制剂处理时对铂类疗法敏感。
从本研究结果来看，我们认为抑制HDAC10可能增强铂类疗法对卵巢肿瘤的疗效。
