Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C
Alexia T. Kedves, … , Michael S. Goldberg, William C. Forrester
Alexia T. Kedves, … , Michael S. Goldberg, William C. Forrester
Published November 13, 2017
Citation Information: J Clin Invest. 2017;127(12):4554-4568. https://doi.org/10.1172/JCI92914.
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Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C

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.

Authors

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

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Figure 2

UBB silencing in gynecological cancers is associated with poor outcomes in HGSOC.

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UBB silencing in gynecological cancers is associated with poor outcomes...
(A) The frequency of decreased UBB expression is shown for each cancer type. The ratio of UBC/UBB mRNA, on a per-patient basis, was determined and the percentage of patients having a UBC/UBB ratio greater than 1.25 is referred to as the silencing rate. A color scheme is used to highlight tumor types with comparable rates of UBB silencing. (B) Analysis of UBB in HGSOC indicates a bimodal distribution of log2(UBB) expression levels based on a Gaussian mixture model, illustrated by kernel density estimates. Dark red color indicates samples within the lowest quartile of expression (dark red = log2[UBB] ≤ Q1, gray = log2[UBB] > Q1). (C) Kaplan-Meier survival curves of HGSOC patient survival stratified by the lowest quartile of UBB expression (dark red) demonstrates significantly poorer outcomes than the patients with higher UBB expression tumors (gray) (P = 0.0138).