CtBP1/2 differentially regulate genomic stability and DNA repair pathway in high-grade serous ovarian cancer cell.
CtBP1/2 differentially regulate genomic stability and DNA repair pathway in high-grade serous ovarian cancer cell.
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DOI：
10.1038/s41389-021-00344-9
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发表时间：
2021-07-13
期刊：
影响因子：
6.2
通讯作者：
Liu S
中科院分区：
文献类型：
--
作者：
He Y;He Z;Lin J;Chen C;Chen Y;Liu S
CtBP 1和CtBP 2是一类转录辅抑制因子，它们与多种转录因子相互作用，调节染色质的稳定性。CtBP蛋白在高级别浆液性卵巢癌（HGSOC）中呈过表达。然而，CtBP蛋白在HGSOC基因组稳定性和DNA修复中的调控作用尚不清楚。在这项研究中，我们将全转录组分析与多种研究方法相结合，以研究CtBP 1/2在基因组稳定性中的作用。通过对CtBP 1/2基因敲低的SKOV 3细胞的全转录谱分析，发现了几个关键的功能途径，包括DNA损伤修复、凋亡和细胞周期。CtBP 1/2基因敲低可诱导肿瘤细胞凋亡，增加遗传不稳定性，增强对DNA损伤剂如γ射线和化疗药物（卡铂和依托泊苷）的敏感性。DNA纤维分析结果表明，CtBP 1/2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。CtBP 1在长时间的复制过程中在代谢应激条件下保护失速叉的完整性，而CtBP 2在DNA复制恢复的稳定性中起主导作用。此外，CtBP 1/2敲低将SKOV 3细胞中的DSB修复途径从同源重组（HR）转移到非同源末端连接（NHEJ）并激活DNA-PK。有趣的是，通过TCGA肿瘤病例的原始细胞，具有CtBP 2基因改变的患者比未改变的患者具有显著更长的总生存时间。总之，这些结果表明，CtBP 1/2在浆液性卵巢癌细胞的基因组稳定性和DSB修复途径偏好中发挥不同的调节作用。这可能产生新的潜在的靶向治疗策略和转化应用于浆液性卵巢癌患者，具有可预测的更好的临床结果。
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.
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影响因子：
8
作者：
Birts, C. N.;Bergman, L. M.;Blaydes, J. P.
通讯作者：
Blaydes, J. P.
DOI：
10.1073/pnas.0830998100
发表时间：
2003-04-15
影响因子：
11.1
作者：
Grooteclaes, M;Deveraux, Q;Frisch, SM
通讯作者：
Frisch, SM
DOI：
10.1038/nrc4019
发表时间：
2015-11
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Bowtell DD;Böhm S;Ahmed AA;Aspuria PJ;Bast RC Jr;Beral V;Berek JS;Birrer MJ;Blagden S;Bookman MA;Brenton JD;Chiappinelli KB;Martins FC;Coukos G;Drapkin R;Edmondson R;Fotopoulou C;Gabra H;Galon J;Gourley C;Heong V;Huntsman DG;Iwanicki M;Karlan BY;Kaye A;Lengyel E;Levine DA;Lu KH;McNeish IA;Menon U;Narod SA;Nelson BH;Nephew KP;Pharoah P;Powell DJ Jr;Ramos P;Romero IL;Scott CL;Sood AK;Stronach EA;Balkwill FR
通讯作者：
Balkwill FR
影响因子：
--
作者：
Bergman LM;Morris L;Darley M;Mirnezami AH;Gunatilake SC;Blaydes JP
通讯作者：
Blaydes JP
DOI：
10.1073/pnas.1315752111
发表时间：
2014-01-07
影响因子：
11.1
作者：
Dose, Marei;Emmanuel, Akinola Olumide;Gounari, Fotini
通讯作者：
Gounari, Fotini