Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C.
J Clin Invest
; 127(12): 4554-4568, 2017 12 01.
Article
em En
| MEDLINE
| ID: mdl-29130934
ABSTRACT
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Inativação Gênica
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Ubiquitina
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Ubiquitina C
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Proteínas de Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Female
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Humans
Idioma:
En
Revista:
J Clin Invest
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos