AbstractFirst, we reanalyzed a large-scale RNA sequencing database (TCGA) comprising 32 cancer types and their corresponding normal tissues. This analysis revealed that in nine cancer types, germ cell lineage pathways were significantly upregulated compared to normal tissues, while conversely, cell-death pathway was suppressed in these cancers. Subsequently, we constructed a custom CRISPR screening library targeting 103 transcription factors expressed exclusively in cancer and germ cells, and conducted CRISPR screening. Through this, we identified TOP2A as a candidate cancer/testis master transcription factor potentially serving as a therapeutic target.Furthermore, by reanalyzing RNA sequencing data obtained using an existing TOP2A inhibitor, we discovered that inhibition of TOP2A leads to reactivation of cell-death pathway. To identify TOP2A’s binding partners that play crucial roles in both the suppression of cell-death pathway and cancer proliferation, we performed a comprehensive analysis based on the following three criteria: “Genes expressed in cancer/testis tissues”, “Genes showing expression correlation with A in clinical samples” and “Proteins confirmed to bind TOP2A via mass spectrometry-based analysis”. Through this approach, we identified three binding proteins: B, C, and D. We then performed protein–protein docking simulations to identify the binding sites of these proteins on TOP2A. Finally, aiming to identify compounds that inhibit these protein–protein interactions (PPIs), we conducted in silico screening of a medium-sized compound library consisting of 10,000 compounds, and identified 100 hit compound candidates for each binding site.岡山大学学術研究院医歯薬学域薬理学分野・教授細野 祥之Yasuyuki HosonoOkayama University― 207 ―癌・生殖細胞ネットワーク内に存在する新たな細胞死誘導経路を標的とした新規抗がん剤開発Development of novel anti-cancer drugstargeting a newly identified cell death-inducing pathwaywithin the cancer–germ cell network
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