Molecular Interplay between AURKA and SPOP Dictates CRPC Pathogenesis via Androgen Receptor
| العنوان: | Molecular Interplay between AURKA and SPOP Dictates CRPC Pathogenesis via Androgen Receptor |
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| المؤلفون: | Asif Raza, Kumar Nikhil, Kavita Shah, Mohini Kamra, Hanan S. Haymour |
| المصدر: | Cancers Volume 12 Issue 11 Cancers, Vol 12, Iss 3247, p 3247 (2020) |
| بيانات النشر: | MDPI, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Cancer Research, SPOP, medicine.disease_cause, lcsh:RC254-282, Article, chemistry.chemical_compound, Downregulation and upregulation, Ubiquitin, medicine, Enzalutamide, Epithelial–mesenchymal transition, CRPC, Aurora kinase A (AURKA), therapy, biology, epithelial to mesenchymal transition, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, prostate cancer, Ubiquitin ligase, Androgen receptor, Oncology, chemistry, biology.protein, Cancer research, Carcinogenesis |
| الوصف: | SPOP, an adaptor protein for E3 ubiquitin ligase can function as a tumor-suppressor or a tumor-enhancer. In castration-resistant prostate cancer (CRPC), it inhibits tumorigenesis by degrading many oncogenic targets, including androgen receptor (AR). Expectedly, SPOP is the most commonly mutated gene in CRPC (15%), which closely correlates with poor prognosis. Importantly, 85% of tumors that retain wild-type SPOP show reduced protein levels, indicating that SPOP downregulation is an essential step in CRPC progression. However, the underlying molecular mechanism remains unknown. This study uncovered the first mechanism of SPOP regulation in any type of cancer. We identified SPOP as a direct substrate of Aurora A (AURKA) using an innovative technique. AURKA directly phosphorylates SPOP at three sites, causing its ubiquitylation. SPOP degradation drives highly aggressive oncogenic phenotypes in cells and in vivo including stabilizing AR, ARv7 and c-Myc. Further, SPOP degrades AURKA via a feedback loop. SPOP upregulation is one of the mechanisms by which enzalutamide exerts its efficacy. Consequently, phospho-resistant SPOP fully abrogates tumorigenesis and EMT in vivo, and renders CRPC cells sensitive to enzalutamide. While genomic mutations of SPOP can be treated with gene therapy, identification of AURKA as an upstream regulator of SPOP provides a powerful opportunity for retaining WT-SPOP in a vast majority of CRPC patients using AURKA inhibitors ± enzalutamide, thereby treating the disease and inhibiting its progression. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2072-6694 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aa9d09d8a8bb3612561840c0bc32878dTest http://europepmc.org/articles/PMC7693105Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....aa9d09d8a8bb3612561840c0bc32878d |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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