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

// Yiqin Wang 1 , Xianrong Zhou 1 , Midie Xu 2, 3, 4, 5 , Weiwei Weng 2, 3, 4, 5 , Qiongyan Zhang 2, 3, 4, 5 , Yusi Yang 2, 3, 4, 5 , Ping Wei 2, 4, 6 , Xiang Du 2, 3, 4, 5 1 Department of Pathology, Obstetrics and Gynecology Hospital of Fudan University, Shanghai 200044, China 2 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai 200032, China 3 Department of Pathology, Shanghai Medical College, Fudan University, Shanghai 200032, China 4 Institute of Pathology, Fudan University, Shanghai 200032, China 5 Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China 6 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China Correspondence to: Ping Wei, e-mail: ripplepz@gmail.com Xiang Du, e-mail: dx2008cn@163.com Keywords: OTUB1, FOXM1, ovarian carcinoma, ubiquitination, deubiquitination Received: August 12, 2015      Accepted: April 22, 2016      Published: May 4, 2016 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.