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CtBP1/2 differentially regulate genomic stability and DNA repair pathway in high-grade serous ovarian cancer cell
Oncogenesis ( IF 5.9 ) Pub Date : 2021-07-13 , DOI: 10.1038/s41389-021-00344-9
YingYing He 1 , Zhicheng He 2, 3 , Jian Lin 2, 3 , Cheng Chen 2, 3 , Yuanzhi Chen 2, 3 , Shubai Liu 2, 3
Affiliation  

The C-terminal binding proteins (CtBPs), CtBP1 and CtBP2, are transcriptional co-repressor that interacts with multiple transcriptional factors to modulate the stability of chromatin. CtBP proteins were identified with overexpression in the high-grade serous ovarian carcinoma (HGSOC). However, little is known about CtBP proteins’ regulatory roles in genomic stability and DNA repair in HGSOC. In this study, we combined whole-transcriptome analysis with multiple research methods to investigate the role of CtBP1/2 in genomic stability. Several key functional pathways were significantly enriched through whole transcription profile analysis of CtBP1/2 knockdown SKOV3 cells, including DNA damage repair, apoptosis, and cell cycle. CtBP1/2 knockdown induced cancer cell apoptosis, increased genetic instability, and enhanced the sensitivity to DNA damage agents, such as γ-irradiation and chemotherapy drug (Carboplatin and etoposide). The results of DNA fiber assay revealed that CtBP1/2 contribute differentially to the integrity of DNA replication track and stability of DNA replication recovery. CtBP1 protects the integrity of stalled forks under metabolic stress condition during prolonged periods of replication, whereas CtBP2 acts a dominant role in stability of DNA replication recovery. Furthermore, CtBP1/2 knockdown shifted the DSBs repair pathway from homologous recombination (HR) to non-homologous end joining (NHEJ) and activated DNA-PK in SKOV3 cells. Interesting, blast through TCGA tumor cases, patients with CtBP2 genetic alternation had a significantly longer overall survival time than unaltered patients. Together, these results revealed that CtBP1/2 play a different regulatory role in genomic stability and DSBs repair pathway bias in serous ovarian cancer cells. It is possible to generate novel potential targeted therapy strategy and translational application for serous ovarian carcinoma patients with a predictable better clinical outcome.



中文翻译:

CtBP1/2差异调节高级别浆液性卵巢癌细胞基因组稳定性和DNA修复途径

C 末端结合蛋白 (CtBP)、CtBP1 和 CtBP2 是转录共阻遏物,可与多种转录因子相互作用以调节染色质的稳定性。在高级别浆液性卵巢癌 (HGSOC) 中发现 CtBP 蛋白过表达。然而,关于 CtBP 蛋白在 HGSOC 基因组稳定性和 DNA 修复中的调节作用知之甚少。在本研究中,我们将全转录组分析与多种研究方法相结合,研究 CtBP1/2 在基因组稳定性中的作用。通过对 CtBP1/2 敲低 SKOV3 细胞的全转录谱分析,显着丰富了几个关键的功能通路,包括 DNA 损伤修复、细胞凋亡和细胞周期。CtBP1/2 敲低诱导癌细胞凋亡,增加遗传不稳定性,并增强了对 DNA 损伤剂的敏感性,例如 γ 辐射和化疗药物(卡铂和依托泊苷)。DNA 纤维测定结果表明 CtBP1/2 对 DNA 复制轨迹的完整性和 DNA 复制恢复的稳定性有不同的贡献。CtBP1 在长时间复制期间保护代谢应激条件下停滞叉的完整性,而 CtBP2 在 DNA 复制恢复的稳定性中起主导作用。此外,CtBP1/2 敲低将 DSBs 修复途径从同源重组 (HR) 转变为非同源末端连接 (NHEJ),并在 SKOV3 细胞中激活 DNA-PK。有趣的是,在 TCGA 肿瘤病例中,具有 CtBP2 基因改变的患者的总生存时间明显长于未改变的患者。一起,这些结果表明,CtBP1/2 在浆液性卵巢癌细胞的基因组稳定性和 DSB 修复途径偏向方面发挥不同的调节作用。有可能为浆液性卵巢癌患者产生新的潜在靶向治疗策略和转化应用,具有可预测的更好临床结果。

更新日期:2021-07-13
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