Abstract
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.
Highlights
Serous ovarian cancer is a gynecological tumor that is more common in women, and high-grade serous ovarian cancer (HGSOC) accounts for roughly 70% of ovarian cancer deaths [1, 2]
Established CtBP1/2 stable knockdown in serous ovarian cancer cells CtBP1/2 was found to be abnormally overexpressed in several ovarian cancer cell lines, including MCAS, SKOV3, RMG1, and RMUGL (Fig. 1A), and a very weak signal was found in human normal ovarian epithelium (HOSE)
The SKOV3 cell was chosen as model to investigate the role of CtBP1/2 in HGSOC by integrated shRNA-based stable knockdown and transcription profiles analysis (Fig. 1B, C)
Summary
Serous ovarian cancer is a gynecological tumor that is more common in women, and high-grade serous ovarian cancer (HGSOC) accounts for roughly 70% of ovarian cancer deaths [1, 2]. As an aggressive tumor type of ovarian cancer, HGSOC had a higher relapse rate (~25%) and poorer overall 5-year survival rate (31%) [3, 4]. The genetic alterations of HGSOC were well characterized, including copying number gains and losses, mutations and deletions [5], and were associated with a homologous recombination (HR) defect and increased sensitivity to DNA damage agents [5, 6]. Intracellular signaling is activated by genetic alterations to detect mispatch and regulate cell cycle progression and promote the repair of DNA lesions by DNA damage response (DDR). Double-strand breaks (DSBs) are among the most lethal types of DNA lesions in mammalian cells, and they are primarily repaired by the nonhomologous end joining (NHEJ) or HR pathways. Pathways for DNA repair disruption, whether through chemotherapy drugs or other clinical cancer treatment methods, had been identified as an effective therapeutic strategy for HGSOC [7, 8]
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