Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C
| Autor: | William C. Forrester, Alexia T. Kedves, Quang-Dé Nguyen, Dennis M. Bonal, Sneha Sanghavi, Prafulla C. Gokhale, Elizabeth George, Fred Harbinski, Robert J. Distel, Paul Kirschmeier, Scott Gleim, Michael S. Goldberg, Christina Benander, Xiaoyou Liang, Jeremy L. Jenkins, Frederic Sigoillot |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
education.field_of_study biology Ubiquitin B Population General Medicine medicine.disease Small hairpin RNA 03 medical and health sciences Ovarian tumor 030104 developmental biology Ubiquitin biology.protein Cancer research medicine Gene silencing Ubiquitin C Ovarian cancer education |
| Zdroj: | Journal of Clinical Investigation. 127:4554-4568 |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci92914 |
| Popis: | Transcriptional repression of ubiquitin B (UBB) is a cancer-subtype-specific alteration that occurs in a substantial population of patients with cancers of the female reproductive tract. UBB is 1 of 2 genes encoding for ubiquitin as a polyprotein consisting of multiple copies of ubiquitin monomers. Silencing of UBB reduces cellular UBB levels and results in an exquisite dependence on ubiquitin C (UBC), the second polyubiquitin gene. UBB is repressed in approximately 30% of high-grade serous ovarian cancer (HGSOC) patients and is a recurrent lesion in uterine carcinosarcoma and endometrial carcinoma. We identified ovarian tumor cell lines that retain UBB in a repressed state, used these cell lines to establish orthotopic ovarian tumors, and found that inducible expression of a UBC-targeting shRNA led to tumor regression, and substantial long-term survival benefit. Thus, we describe a recurrent cancer-specific lesion at the level of ubiquitin production. Moreover, these observations reveal the prognostic value of UBB repression and establish UBC as a promising therapeutic target for ovarian cancer patients with recurrent UBB silencing. |
| Databáze: | OpenAIRE |
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