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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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Research Article Genetics Oncology Article has an altmetric score of 13

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

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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 6

UBB and UBC are a synthetic lethal gene pair.

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UBB and UBC are a synthetic lethal gene pair.
(A) OC316 (black, UBBWT) ...
(A) OC316 (black, UBBWT) and OVCAR8 (red, UBBLO) cells were transfected with a combination of 2 siRNAs for each of UBB and UBC at 5 nM each as shown in the matrix below the figure. Individual siRNAs for UBC or UBB were combined with a nontargeting siRNA (NT) or with each other and viability (CellTiter-Glo assay) was determined 72 hours after transfection. The study was performed twice as biological quadruplicates and the results are shown as mean ± SEM. (B and C) Measurement of siRNA-mediated knockdown of mRNA for (B) UBB and (C) UBC as log2 fold-change relative to OC316 siNT control (far left sample) 24 hours after transfection among biological quadruplicates, with mean ± SEM and performed twice. (D) Colony formation assays of OVCAR8 containing a doxycycline-inducible (Dox-inducible) UBC shRNA transfected with a neomycin-resistance plasmid encoding UBB (pUBB) or the empty vector alone (pVec). Antibiotic-resistant cells were seeded into 6-well plates with or without Dox (100 ng/ml) and 7 days later cells were fixed and stained with crystal violet. This study was performed twice. (E) Expression from pUBB was measured on 3 successive days after addition of Dox. Analysis of technical replicates with SD of the mean was performed twice.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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