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

Fangzhou Li,Wei Gu,Jun Qin,Zebin Mao,Ning Kon,Kun Liu,Ling Zhang,Tanjun Tong,Dawei Li,Ning Lin,Qianqian Sun,Mingwei Liu,Feng Tian,Wenhui Zhao,Tingting Li,Kaiqiang You

doi:10.1038/s41467-020-17926-7

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.

Highlights

Oncogenic processes exert their greatest effect by targeting regulators of cell proliferation
The results of the colony formation assay showed that the knockdown of 8 of 14 ovarian tumor (OTU) DUBs reduced the number of Hep3B cell colonies, whereas knockdown of 3 of 14 candidates promoted colony formation of the Hep3B cells
The results demonstrated that the TRIM25-KR mutant inhibited cell growth, consistently, cells with increased OTUD5 expression formed fewer colonies than the control cells (Supplementary Fig. 2C, D), implying that the autoubiquitination of TRIM25 is crucial for its function in cell proliferation regulation

Summary

Introduction

Oncogenic processes exert their greatest effect by targeting regulators of cell proliferation. 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. OTUD5 knockdown accelerates tumor growth in a nude mouse model. 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. The OTU subfamily of DUBs have been the focus of many studies and shown to function in numerous cellular processes[3].

Methods

Results

Conclusion