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CDCA5 promotes the progression of prostate cancer by affecting the ERK signalling pathway.

ABSTRACT: Cell division cycle-associated 5 (CDCA5) can regulate cell cycle-related proteins to promote the proliferation of cancer cells. The purpose of the present study was to investigate the expression level of CDCA5 in prostate cancer (PCa) and its effect on PCa progression. The signalling pathway by which CDCA5 functions through was also attempted to elucidate. Clinical specimens of PCa patients were collected from the Second Hospital of Tianjin Medical University. The expression level of CDCA5 in cancer tissues and paracancerous tissues from PCa patients was detected by RT-qPCR analysis and IHC. The relationship between the expression level of CDCA5 and the survival rate of PCa patients was analysed using TCGA database. Two stable cell lines (C4-2 and PC-3) with CDCA5 knockdown were established, and the effects of CDCA5 on PCa cell proliferation were detected by MTT and colony formation assays. Flow cytometry was performed to detect the effect of CDCA5 on the PCa cell division cycle, and western blot analysis was used to determine changes in ERK phosphorylation levels after CDCA5 knockdown. The effect of CDCA5 expression on prostate tumour growth was assessed using a mouse xenograft model. The results revealed that the mRNA and protein expression levels of CDCA5 were significantly higher in PCa tissues than in paracancerous tissues. High CDCA5 expression was associated with the prognosis of patients with PCa. CDCA5 expression knockdown significantly reduced the number of PCa cells in mitoses and inhibited their proliferation in vitro and in vivo. When CDCA5 was knocked down, the phosphorylation level of ERK was also reduced. Collectively, CDCA5 was upregulated and affected the prognosis of patients with PCa. Decreased CDCA5 expression inhibited PCa cell proliferation by inhibiting the ERK signalling pathway. Thus, CDCA5 may be a potential therapeutic target for PCa.

SUBMITTER: Ji J

PROVIDER: S-EPMC7859918 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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CDCA5 promotes the progression of prostate cancer by affecting the ERK signalling pathway.

Ji Junpeng J Shen Tianyu T Li Yang Y Liu Yixi Y Shang Zhiqun Z Niu Yuanjie Y

Oncology reports 20210104 3

Cell division cycle-associated 5 (CDCA5) can regulate cell cycle-related proteins to promote the proliferation of cancer cells. The purpose of the present study was to investigate the expression level of CDCA5 in prostate cancer (PCa) and its effect on PCa progression. The signalling pathway by which CDCA5 functions through was also attempted to elucidate. Clinical specimens of PCa patients were collected from the Second Hospital of Tianjin Medical University. The expression level of CDCA5 in ca ...[more]

PMID: 33650660

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Project description:BackgoundColorectal cancer (CRC) is a complex, multistep disease that arises from the interplay genetic mutations and epigenetic alterations. The histone H3K36 trimethyltransferase SET domain-containing 2 (SETD2), as an epigenetic signalling molecule, has a 5% mutation rate in CRC. SETD2 expression is decreased in the development of human CRC and mice treated with Azoxymethane /Dextran sodium sulfate (AOM/DSS). Loss of SETD2 promoted CRC development. SMAD Family member 4 (SMAD4) has a 14% mutation rate in CRC, and SMAD4 ablation leads to CRC. The co-mutation of SETD2 and SMAD4 predicted advanced CRC. However, little is known on the potential synergistic effect of SETD2 and SMAD4.MethodsCRC tissues from mice and SW620 cells were used as research subjects. Clinical databases of CRC patients were analyzed to investigate the association between SETD2 and SMAD4. SETD2 and SMAD4 double-knockout mice were established to further investigate the role of SETD2 in SMAD4-deficient CRC. The intestinal epithelial cells (IECs) were isolated for RNA sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) to explore the mechanism and the key molecules resulting in CRC. Molecular and cellular experiments were conducted to analyze the role of SETD2 in SMAD4-deficient CRC. Finally, rescue experiments were performed to confirm the molecular mechanism of SETD2 in the development of SMAD4-dificient CRC.ResultsThe deletion of SETD2 promotes the malignant progression of SMAD4-deficient CRC. Smad4Vil-KO ; Setd2Vil-KO mice developed a more severe CRC phenotype after AOM/DSS induction, with a larger tumour size and a more vigorous epithelial proliferation rate. Further mechanistic findings revealed that the loss of SETD2 resulted in the down-regulation of DUSP7, which is involved in the inhibition of the RAS/ERK signalling pathway. Finally, the ERK1/2 inhibitor SCH772984 significantly attenuated the progression of CRC in Smad4Vil-KO ;Setd2Vil-KO mice, and overexpression of DUSP7 significantly inhibited the proliferation rates of SETD2KO ; SMAD4KO SW620 cells.ConclusionsOur results demonstrated that SETD2 inhibits the RAS/ERK signaling pathway by facilitating the transcription of DUSP7 in SMAD4-deficient CRC, which could provide a potential therapeutic target for the treatment of advanced CRC.

Dataset Information

CDCA5 promotes the progression of prostate cancer by affecting the ERK signalling pathway.

Publications

CDCA5 promotes the progression of prostate cancer by affecting the ERK signalling pathway.

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