Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin, 300211, China.
Vancouver Prostate Centre, Department of Urologic Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC V6H 3Z6, Canada; Department of Experimental Therapeutics, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada.
Gene. 2020 Jun 20;744:144608. doi: 10.1016/j.gene.2020.144608. Epub 2020 Mar 29.
Prostate cancer (PCa) is the third most common malignancy worldwide. Novel and effective therapeutic targets are needed for PCa. The purpose of this study was to discover novel therapeutic targets for PCa by performing advanced analysis on PCa RNA sequencing (RNAseq) data from The Cancer Genome Atlas (TCGA). Weighted correlation-network analysis (WGCNA) was performed on the RNAseq data of tumor samples, and the module most relevant to the Gleason score was identified. Combining differential gene-expression analysis and survival analysis, we narrowed down potential therapeutic target genes and found that PKMYT1 might be one. Subsequently, functional studies (i.e., cell-proliferation assays, cell cycle analysis, and colony-formation assays) demonstrated that knockdown of PKMYT1 significantly inhibited the growth of PCa cells. Further investigation illustrated that PKMYT1 promoted the growth of PCa cells through targeting CCNB1 and CCNE1 expression. In addition, fostamatinib, an inhibitor of PKMYT1, effectively inhibited the proliferation of PCa cells. Taken together, our results suggest that PKMYT1 is a gene associated with malignancy of PCa and is a novel therapeutic target.
前列腺癌(PCa)是全球第三大常见恶性肿瘤。需要寻找新的、有效的治疗靶点来治疗 PCa。本研究旨在通过对癌症基因组图谱(TCGA)的 PCa RNA 测序(RNAseq)数据进行高级分析,来发现治疗 PCa 的新靶点。对肿瘤样本的 RNAseq 数据进行加权相关网络分析(WGCNA),并确定与 Gleason 评分最相关的模块。结合差异基因表达分析和生存分析,我们缩小了潜在的治疗靶点基因的范围,并发现 PKMYT1 可能是其中之一。随后,功能研究(即细胞增殖试验、细胞周期分析和集落形成试验)表明,PKMYT1 的敲低显著抑制了 PCa 细胞的生长。进一步的研究表明,PKMYT1 通过靶向 CCNB1 和 CCNE1 的表达促进了 PCa 细胞的生长。此外,PKMYT1 的抑制剂 fostamatinib 有效地抑制了 PCa 细胞的增殖。综上所述,我们的研究结果表明,PKMYT1 是与 PCa 恶性程度相关的基因,是一个新的治疗靶点。