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

Fangzhou Li, Qianqian Sun, Kun Liu, Ling Zhang, Ning Lin, Kaiqiang You, Mingwei Liu, Ning Kon, Feng Tian, Zebin Mao, Tingting Li, Tanjun Tong, Jun Qin, Wei Gu, Dawei Li () and Wenhui Zhao ()
Additional contact information
Fangzhou Li: Peking University Health Science Center
Qianqian Sun: Peking University Health Science Center
Kun Liu: Peking University Health Science Center
Ling Zhang: The Affiliated Zhangjiagang Hospital of Soochow University
Ning Lin: Peking University Health Science Center
Kaiqiang You: Peking University Health Science Center
Mingwei Liu: Beijing Proteome Research Center
Ning Kon: Columbia University
Feng Tian: Peking University Health Science Center
Zebin Mao: Peking University Health Science Center
Tingting Li: Peking University Health Science Center
Tanjun Tong: Peking University Health Science Center
Jun Qin: Beijing Proteome Research Center
Wei Gu: Columbia University
Dawei Li: The Affiliated Zhangjiagang Hospital of Soochow University
Wenhui Zhao: Peking University Health Science Center

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-17926-7

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