Dataset Information

CDCA8, targeted by MYBL2, promotes malignant progression and olaparib insensitivity in ovarian cancer.

ABSTRACT: Ovarian cancer is the most lethal gynecologic malignancy. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective in treating ovarian cancer. However, cancer cell insensitivity and resistance remain challenges. Determination of the exact chemoresistance mechanisms and potential targeted therapies is urgent. CDCA8 (cell division cycle associated 8) participates in the tumorigenesis of various cancers; however, the exact biological function of CDCA8 in ovarian cancer remains obscure. Here, we found that CDCA8 was overexpressed in ovarian cancer and that high expression of CDCA8 promoted the proliferation of ovarian cancer cells in vitro and in vivo. Moreover, silencing of CDCA8 sensitized ovarian cancer cells to olaparib and cisplatin by inducing G2/M arrest, accelerating apoptosis, increasing DNA damage and interfering with RAD51 accumulation in vitro. In addition, MYBL2 (MYB proto-oncogene-like 2), identified as an upstream transcription factor of CDCA8, was positively correlated with the expression level of CDCA8 in ovarian cancer. Finally, MYBL2 enhanced the aggressive characteristics of ovarian cancer cells by regulating CDCA8. In conclusion, high CDCA8 expression was involved in the tumorigenesis, aggressiveness and chemoresistance of ovarian cancer. CDCA8 silencing combined with olaparib treatment might lead to substantial progress in ovarian cancer targeted therapy.

SUBMITTER: Qi G

PROVIDER: S-EPMC7868764 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

CDCA8, targeted by MYBL2, promotes malignant progression and olaparib insensitivity in ovarian cancer.

Qi Gonghua G Zhang Chenyi C Ma Hanlin H Li Yingwei Y Peng Jiali J Chen Jingying J Kong Beihua B

American journal of cancer research 20210201 2

Ovarian cancer is the most lethal gynecologic malignancy. Poly (ADP-ribose) polymerase inhibitors (PARPi) are effective in treating ovarian cancer. However, cancer cell insensitivity and resistance remain challenges. Determination of the exact chemoresistance mechanisms and potential targeted therapies is urgent. CDCA8 (cell division cycle associated 8) participates in the tumorigenesis of various cancers; however, the exact biological function of CDCA8 in ovarian cancer remains obscure. Here, w ...[more]

PMID: 33575078

Similar Datasets

Project description:BackgroundOvarian cancer is the most lethal gynecologic malignancy worldwide. Olaparib, an inhibitor of poly (ADP-ribose) polymerase (PARP), is becoming widely used in ovarian cancer treatment. The overall survival of ovarian cancer has not been significantly changed over the past decades and ovarian cancer has become increasingly resistant to the Olaparib. Ubiquitin-conjugating enzyme E2S (UBE2S) has been proved to promote malignant behaviors in many cancers. However, the function of UBE2S in the development and Olaparib resistance of ovarian cancer are unclear.Materials and methodsIn this study, we detected the expression of UBE2S in normal fallopian tube (FT) and HGSOC tissues. A2780 and SKOV3 cells were stably transfected with PCMV-UBE2S, PCMV-UBE2S-C95S, UBE2S shRNAs, and negative controls. The CCK8 assay and clonogenic assay were conducted to analyze ovarian cancer proliferation and Olaparib resistance. The transwell assay was performed to determine the migration and invasion of ovarian cancer cells. The relative protein levels of the Wnt/β-catenin signaling pathway were tested using western blot. The ovarian cancer cells were treated with XAV-939 to investigate the role of Wnt/β-catenin signaling pathway in Olaparib resistance. Moreover, we repeated some above procedures in the xenograft model.ResultsThe results demonstrated that UBE2S was highly upregulated in HGSOC and that high UBE2S expression was correlated with poor outcomes in HGSOC. UBE2S promoted ovarian cancer proliferation and drived the migration and invasion of ovarian cancer cells. UBE2S activated the Wnt/β-catenin signaling pathway in ovarian cancer resulting in Olaparib resistance in vitro and in vivo. Furthermore, UBE2S enhanced the proliferation and Olaparib resistance of ovarian cancer in its enzymatic activity dependent manner.ConclusionsThese data suggest a possible molecular mechanism of proliferation and metastasis of ovarian cancer and highlight the potential role of UBE2S as a therapeutic target in ovarian cancer.

Project description:MYB-related protein B (B-MYB/MYBL2), a member of the myeloblastosis family of transcription factors, has been reported for its role in the genesis and progression of tumors. Forkhead box M1 (FoxM1), another transcriptional factor, is considered to be an independent predictor of poor survival in many solid cancers. The aim of the present study was to investigate the clinical significance of the correlation between MYBL2 and FoxM1 in glioma and the possible mechanism of FoxM1and MYBL2 expression.MYBL2 and FoxM1expression in cancerous tissues and cell lines were determined by reverse transcription-PCR (RT-PCR), Western blotting and immunostaining. The co-expression of MYBL2 and FoxM1 was analyzed in low-grade glioma (LGG) and glioblastoma (HGG) cohorts of TCGA using cBioportal and UCSC Xena. And, the role of MYBL2 and FoxM1 in glioma cell progression and the underlying mechanisms were studied by using small interfering RNA (si-RNA) and pcDNA3.1 + HAvectors. Furthermore, the effects of MYBL2 and FoxM1 in cell proliferation, cell cycle progression, apoptosis, migration, invasion, and adhesion were determined by cell proliferation assays, flow cytometry analysis, transwell migration and cell adhesion assay.MYBL2 and FoxM1 expression are significantly associated with clinical stages and overall survival of glioma patients. In cohorts of TCGA, patients with high MYBL2 but without radio-chemotherapy had the highest hazard ratio (adjusted HR = 5.29, 95% CI = 1.475-18.969, P < 0.05). Meanwhile, MYBL2 closely related to the FoxM1 expression in 79 glioma tissues (r = 0.742, p < 0.05) and LGG (r = 0.83) and HGG (r = 0.74) cohorts of TCGA. Down regulation of FoxM1 and MYBL2 by siRNAs induced the cell cycle arrest, apoptosis and EMT of glioma cells. Furthermore, inactivations of Akt/FoxM1 signaling by Akt inhibitor and siRNA-FoxM1 reduce the expression of MYBL2 in glioma cells.MYBL2 is a key downstream factor of Akt/FoxM1 signaling to promote progression of human glioma, and could be a new candidate gene for molecular targeting therapy and biomarker for radiotherapy of glioma.CTXY-1300041-3-2. ChiCTR-COC-15006186 . Registered date: 13 September 2013.

Dataset Information

CDCA8, targeted by MYBL2, promotes malignant progression and olaparib insensitivity in ovarian cancer.

Publications

CDCA8, targeted by MYBL2, promotes malignant progression and olaparib insensitivity in ovarian cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets