Recurrent ubiquitin B silencing in gynecological cancers establishes dependence on ubiquitin C
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
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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Research Article Genetics Oncology

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 1

TCGA analysis identifies UBB silencing in HGSOC.

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TCGA analysis identifies UBB silencing in HGSOC. (A) Expression of the 4...
(A) Expression of the 4 human genes that encode for ubiquitin — RPS27A (yellow), UBA52 (blue), UBB (red), and UBC (green) — along with GAPDH (gray), in 3 TCGA tumor types — lung (LUAD), ovarian (OV), and thyroid (THCA). RNASeq data are displayed as gene-level log2RSEM values. Each data point represents a patient-specific RNA level for the indicated gene, with violin plot profiles indicating the derived probability density of each population. (B) UBB expression and DNA methylation in subtypes previously established by TCGA is shown in the top and bottom panels, respectively. Subtypes defined based on transcriptional signatures are immunoreactive (I), mesechymal (M), differentiated (D), and proliferative (P). Methylation levels are reported as β values from 0 (no methylation) to 1.0 (full methylation). (C) Correlation plots and corresponding P values show subtype-specific methylation and expression of UBB (associated Pearson R2 and P values: immunoreactive = –0.66, 6.8 e–21; mesenchymal = –0.69, 2.5e–14; differentiated = –0.74, 1.6e–25; proliferative = –0.84, 2.3e–46). Colors by transcriptional subtype correspond to B.