OTUD5 cooperates with TRIM25 in transcriptional regulation and tumor progression via deubiquitination activity

Abstract

Oncogenic processes exert their greatest effect by targeting regulators of cell proliferation. Studying the mechanism underlying growth augmentation is expected to improve clinical therapies. The ovarian tumor (OTU) subfamily deubiquitinases have been implicated in the regulation of critical cell-signaling cascades, but most OTUs functions remain to be investigated. Through an unbiased RNAi screen, knockdown of OTUD5 is shown to significantly accelerate cell growth. Further investigation reveals that OTUD5 depletion leads to the enhanced transcriptional activity of TRIM25 and the inhibited expression of PML by altering the ubiquitination level of TRIM25. Importantly, OTUD5 knockdown accelerates tumor growth in a nude mouse model. OTUD5 expression is markedly downregulated in tumor tissues. The reduced OTUD5 level is associated with an aggressive phenotype and a poor clinical outcome for cancers patients. Our findings reveal a mechanism whereby OTUD5 regulates gene transcription and suppresses tumorigenesis by deubiquitinating TRIM25, providing a potential target for oncotherapy.

Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation

“…S6C). In contrast, we found that TRIM25 and TRAF3, two previously described K63-ubiquitin chain–modified substrates of OTUD5 ( 41 , 62 ), are dispensable for neural conversion ( Fig. 5E and fig.…”

Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress

“…We identified 51, 87, and 73 potential direct RFX7 targets in U2OS, HCT116, and RPE-1 cells, respectively, and these direct RFX7 targets include PDCD4 , PIK3IP1 , MXD4 , and PNRC1 (Figure 4D). Most strikingly, target genes up-regulated through the p53-RFX7 axis comprise additional tumor suppressor genes, such as ABAT (65), CCNG2 (66), IP6K2 (67), OTUD5 (68), REV3L (69), RPS6KA5 (also known as MSK1 ) (70), TOB1 (71), TSC22D1 (72), and TSPYL2 (73). Most direct RFX7 targets were up-regulated in response to Nutlin-3a treatment in siControl-transfected cells, and the up-regulation was impaired or abrogated when RFX7 was depleted (Figure 4D).…”

STAMBP promotes lung adenocarcinoma metastasis by regulating the EGFR/MAPK signaling pathway

“…Accumulating evidence implicates DUBs in tumorigenesis and progression at multiple levels [38] . Our study indicates that OTUD5, a member of the ovarian tumor protease (OTU) subfamily of DUBs, cooperates with TRIM25 in tumor suppression via deubiquitination activity [37] . The proteasome DUBs PSMD14 and UCHL5 are implicated in LUAD progression through the regulation of cell cycle proteins [ 36 , 39 ].…”

“…The tissues were formalin-fixed and paraffin-embedded. IHC staining was performed using the peroxidase technique, as previously described [37] . Briefly, the sections were cut into 4 µm slices, deparaffinized and rehydrated.…”

“…The mice were euthanized 6 wk after tumor implantation. The lung tumor was dissected and tumor volume was calculated as previously described [37] by the formula V =π × L × W 2 /6, where L represents the longest dimension and W the shortest dimension of the tumor. The number of metastasis lesions on the surface of chest wall was counted before pathological analysis.…”