Clarification of mechanisms regulating AR-V7 in castration resistant prostate cancer
| Project/Area Number |
18K16732
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 56030:Urology-related
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 前立腺癌 / 去勢抵抗性前立腺癌 / 癌治療 / 癌 / スプライシング |
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| Outline of Final Research Achievements |
Androgen receptor splice variant-7 (AR-V7) is a constitutively active AR variant implicated in castration-resistant prostate cancers. Here, we show that the RNA splicing factor SF3B2, identified by in silico and CRISPR/Cas9 analyses, is a critical determinant of AR-V7 expression and is correlated with aggressive cancer phenotypes. Transcriptome and PAR-CLIP analyses revealed that SF3B2 controls the splicing of target genes, including AR, to drive aggressive phenotypes. SF3B2-mediated aggressive phenotypes in vivo were reversed by AR-V7 knockout. Pladienolide B, an inhibitor of a splicing modulator of the SF3b complex, suppressed the growth of tumors addicted to high SF3B2 expression. These findings support the idea that alteration of the splicing pattern by high SF3B2 expression is one mechanism underlying prostate cancer progression and therapeutic resistance. This study also provides evidence supporting SF3B2 as a candidate therapeutic target for treating patients with cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
去勢抵抗性前立腺癌の薬剤抵抗性マーカーと考えられているAR-V7が発現する原因の一つとして、SF3B2を同定した。さらには、遺伝子発現解析やPAR-CLIPなどの最先端の技術を用いて、SF3B2が癌の進展に寄与するメカニズムを明らかにした（スプライシングの調節、遺伝子発現の調節）。またSF3B複合体を抑制する化合物PladienolideBが、癌の増殖を抑制することが明らかになり、SF3B2が新たな治療標的となりうることが明らかになった。
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Report
(3 results)
Research Products
(3 results)
