Journal of Clinical Investigation
Journal of Clinical Investigation
5 years ago

Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C.

Sneha Sanghavi, Quang-De Nguyen, Prafulla C Gokhale, Frederic Sigoillot, Jeremy Jenkins, Robert J Distel, Paul T Kirschmeier, Xiaoyou Liang, Elizabeth George, Michael S Goldberg, Christina Benander, Fred Harbinski, Scott Gleim, William C Forrester, Dennis M Bonal, Alexia T Kedves
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.

Publisher URL: http://doi.org/10.1172/JCI92914

DOI: 10.1172/JCI92914

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