Application of the degradation system for ETV1 to prostate cancer therapy

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K18613
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Ehime University
• Principal Investigator: WATANABE RYUTA 愛媛大学, 医学部附属病院, 助教 (00813635)
• Project Period (FY): 2020-03-01 – 2022-03-31
• Keywords: 前立腺癌 / SPOP / TMPRSS-ERG融合遺伝子 / ETV1 / DNA修復 / TOP2A / TOP阻害剤 / TDP1/2

Outline of Final Research Achievements

SPOP is the most frequently mutated gene in prostate cancer patients (10-15%), and regulates ubiquitination and degradation of substrate proteins. More than 30 substrate proteins, represented by AR and ERG, have been identified.We detected ETV1, which forms a fusion gene with TMPRSS2 as in ERG, as a candidate substrate protein by alpha screen analysis. However, no evidence was obtained that ETV1 is a substrate protein of SPOP. On the other hand, we found that SPOP promotes prostate cancer progression by inducing genomic instability through TOP2A. Furthermore, we found that TOP inhibitors and PARP inhibitors may be effective for patients with SPOP-mutant prostate cancer.

Free Research Field

前立腺癌

Academic Significance and Societal Importance of the Research Achievements

SPOP変異はARを代表とする基質蛋白質の蓄積の結果、前立腺癌を進行に導くとされてきた。我々の研究により、SPOP変異はTOP2Aを介してゲノム不安定性を誘導することで前立腺癌を増悪させることを明らかにした。過去にTMPRSS2-ERG融合遺伝子がTOP2B-AR複合体によるゲノム不安定性にて形成されることが報告されており、今回SPOP変異経路とTMPRSS2-ERG融合遺伝子経路という相互排他的な２経路が前立腺癌において存在することを突き止めた。これらの経路を理解することで、今後TOP阻害剤、PARP阻害剤、SPOP阻害剤といった治療薬のプレシジョンメディシンにつながる可能性が期待できる。