Dataset Information

Identification and Validation of Three Hub Genes Involved in Cell Proliferation and Prognosis of Castration-Resistant Prostate Cancer.

ABSTRACT:

Background

The acquisition of castration resistance is lethal and inevitable in most prostate cancer patients under hormone therapy. However, effective biomarkers and therapeutic targets for castration-resistant prostate cancer remain to be defined.

Methods

Comprehensive bioinformatics tools were used to screen hub genes in castration-resistant prostate cancer and were verified in androgen-dependent prostate cancer and castration-resistant prostate cancer in TCGA and the SU2C/PCF Dream Team database, respectively. Gene set enrichment analysis and in vitro experiments were performed to determine the potential functions of hub genes involved in castration-resistant prostate cancer progression.

Results

Three hub genes were screened out by bioinformatics analysis: MCM4, CENPI, and KNTC1. These hub genes were upregulated in castration-resistant prostate cancer and showed high diagnostic and prognostic value. Moreover, the expression levels of the hub genes were positively correlated with neuroendocrine prostate cancer scores, which represent the degree of castration-resistant prostate cancer aggression. Meanwhile, in vitro experiments confirmed that hub gene expression was increased in castration-resistant prostate cancer cell lines and that inhibition of hub genes hindered cell cycle transition, resulting in suppression of castration-resistant prostate cancer cell proliferation, which confirmed the gene set enrichment analysis results.

Conclusions

MCM4, CENPI, and KNTC1 could serve as candidate diagnostic and prognostic biomarkers of castration-resistant prostate cancer and may provide potential preventive and therapeutic targets.

SUBMITTER: Yu P

PROVIDER: S-EPMC9402298 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

Identification and Validation of Three Hub Genes Involved in Cell Proliferation and Prognosis of Castration-Resistant Prostate Cancer.

Yu Pan P Dai Yibei Y Zhuang Tingting T Yue Xiaofang X Chen Yuhua Y Wang Xuchu X Duan Xiuzhi X Ping Ying Y Xie Yiyi Y Cao Ying Y Tao Zhihua Z

Oxidative medicine and cellular longevity 20220817

<h4>Background</h4>The acquisition of castration resistance is lethal and inevitable in most prostate cancer patients under hormone therapy. However, effective biomarkers and therapeutic targets for castration-resistant prostate cancer remain to be defined.<h4>Methods</h4>Comprehensive bioinformatics tools were used to screen hub genes in castration-resistant prostate cancer and were verified in androgen-dependent prostate cancer and castration-resistant prostate cancer in TCGA and the SU2C/PCF ...[more]

PMID: 36035209

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Project description:Rationale: Prostate cancer is one of the most common malignant tumors occurring in the male reproductive system. Androgen deprivation therapy (ADT) is the primary treatment for prostate cancer. However, approximately 10% to 20% of advanced prostate cancer patients progress to castration-resistant prostate cancer (CRPC) within five years, posing a significant challenge to treatment. There is an urgent need to explore the causes and mechanisms of prostate cancer progression, and to identify new therapeutic targets and predictive markers.Methods: Utilize RNA-seq to screen for differentially expressed genes and alternative splicing events between androgen-sensitive prostate cancer cells and castration-resistant prostate cancer cells. Perform bioinformatics analysis on the differentially expressed genes. The expression levels of these genes were confirmed by real-time quantitative PCR (RT-qPCR); alternative splicing events related to castration resistance were verified through RT-PCR. The impact of the S100A6 gene on the proliferation and growth capabilities of PC3 and DU145 cells was analyzed using CCK8, colony formation, and EdU assays. Cell migration was assessed using a wound healing assay.Results: The RNA-seq analysis results showed that there were 4,830 differentially expressed genes in non-hormone-sensitive prostate cancer. GO and KEGG enrichment analysis of these differentially expressed genes revealed significant enrichment in tumor-related signaling pathways such as regulation of cell cycle process, cell division, and regulation of cell projection organization. Further RT-qPCR detection results indicated that the mRNA expression of four genes, including S100A6, was upregulated, consistent with the transcriptome sequencing results. Downregulation of S100A6 expression significantly inhibited the proliferation and migration of non-hormone-dependent prostate cancer. In this study, we also identified many splicing alterations in cancer-related genes, with castration resistance-induced alternative splicing events closely related to the interaction networks of regulation of cell cycle process, cell division, and regulation of cell projection organization.Conclusions: Our research findings suggest that S100A6 may serve as a molecular marker or therapeutic target associated with castration resistance in prostate cancer, providing new insights into the molecular basis of this disease.

Project description:BackgroundMetastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated.ObjectiveTo use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance.Design, setting, and participantsWe performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients.Outcome measurements and statistical analysisOS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test.Results and limitationsHarboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0mo; p=0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p=0.01) and independently predictive of poor OS (median 13.6 vs 41.7mo; p=0.025).ConclusionsThe presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort.Patient summaryWe observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.

Project description:Backgroundc-Myc, a well-established oncogene, plays an important role in the initiation and progression of various cancers, including prostate cancer. However, its mechanism in cancer cell remains largely unknown and whether there exist a deubiquitinase targeting c-Myc also remains elusive.MethodsBioinformatic analysis and shRNA screening methods were used to identify potential deubiquitinases that correlate with c-Myc gene signature. Cell proliferation and viability were measured by Cell-Counting-Kit 8 and colony formation assays. A mouse xenograft model of PC3 cells was established to confirm the function of USP16 in vivo. The interaction between USP16 and c-Myc protein was assessed by co-immunoprecipitation and protein co-localization assays. Immunohistochemistry staining was performed to detect the expression of USP16, Ki67, and c-Myc in xenograft tissues and clinical tumour tissues. Furthermore, the correlation between USP16 and c-Myc was confirmed by RNA sequencing.ResultsFunctional analyses identified USP16, known as a deubiquitinase, was strongly correlated with the c-Myc gene signature. Depletion of USP16 was shown to significantly suppress the growth of PCa cells both in vitro and in vivo. Co-immunoprecipitation and ubiquitination assays confirmed that USP16 served as a novel deubiquitinase of c-Myc and overexpression of c-Myc significantly rescued the effects of USP16 disruption. Immunohistochemistry staining and RNA-seq tactics were further used to confirm the positive correlation between USP16 and c-Myc expression. Expression of USP16 in human PCa tissues was higher than that seen in normal prostate tissues and its high expression was found associated with poor prognosis.ConclusionsUSP16 serves as a novel deubiquitinase of c-Myc. Downregulation of USP16 markedly suppressed PCa cell growth both in vitro and in vivo. USP16 regulates PCa cell proliferation by deubiquitinating and stabilizing c-Myc, making it a potential therapeutic candidate for the treatment of PCa.

Dataset Information

Identification and Validation of Three Hub Genes Involved in Cell Proliferation and Prognosis of Castration-Resistant Prostate Cancer.

Background

Methods

Results

Conclusions

Publications

Identification and Validation of Three Hub Genes Involved in Cell Proliferation and Prognosis of Castration-Resistant Prostate Cancer.

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