OTUB1-catalyzed deubiquitination of FOXM1 facilitates tumor progression and predicts a poor prognosis in ovarian cancer

Yiqin Wang,Xianrong Zhou,Qiongyan Zhang,Yusi Yang,Weiwei Weng,Midie Xu,Xiang Du,Ping Wei

doi:10.18632/oncotarget.9160

Abstract

Ubiquitination is essential for regulation of cell physiology, protein stability, and signal transduction [1]. Its dysregulation is an important factor in many diseases, including cancer. We explored the potential OTUB1-catalyzed deubiquitination of FOXM1, a transcription factor linked to carcinogenesis, and the biological consequence of that interaction in ovarian cancer. We found that FOXM1 is ubiquitinated by multiple polyUb chains and targeted for proteosomal degradation in a reaction dependent on its ubiquitination-required KEN box. Additionally, the OTUB1 N-terminus and catalytic triad bind to FOXM1, specifically catalyzing cleavage of the K48-specific ubiquitin linkage from FOXM1. Moreover, OTUB1-FOXM1 interaction drives tumor progression and OTUB1 expression predicts a poor prognosis in ovarian cancer. Our study suggests that inhibiting OTUB1-FOXM1 interaction is a potential new avenue for ovarian cancer therapy.

Highlights

In the process of ubiquitination, ubiquitin (Ub), a 76 amino acid protein, is conjugated to the lysine residues of specific substrate proteins via the transfer from E1 activating enzyme to E2 conjugating enzyme and subsequent binding catalyzed by E3 ligase [2]
These results strongly suggest that OTUB1 interacts with FOXM1
Our study shows that OTUB1, highly expressed in ovarian cancer, binds to FOXM1 and cleaves the K48linked polyUb chain, stabilizing FOXM1 to promote tumorigenesis and tumor progression

Summary

Introduction

In the process of ubiquitination, ubiquitin (Ub), a 76 amino acid protein, is conjugated to the lysine residues of specific substrate proteins via the transfer from E1 activating enzyme to E2 conjugating enzyme and subsequent binding catalyzed by E3 ligase [2]. Ub contains seven lysine residues for conjugation, each of which can form a specific polyubiquitin (polyUb) chain with distinct functions. The classic linkages such as K48- and K11-lead to proteosomal degradation of the substrate protein while K63-functions in signal transduction [3]. DUBs enable reciprocal biological functions by catalyzing deubiquitination of crucial proteins [2]. FOXM1 is a predicted target of the ubiquitinproteosome system [13,14,15], little is known about either its degradation-related domains or its affinity for different polyUb chains

Methods

Results

Conclusion