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

Oncotarget. 2016 Jun 14;7(24):36681-36697. 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.

Keywords: FOXM1; OTUB1; deubiquitination; ovarian carcinoma; ubiquitination.

MeSH terms

  • Adult
  • Biocatalysis
  • Cell Line, Tumor
  • Cysteine Endopeptidases / genetics
  • Cysteine Endopeptidases / metabolism*
  • Deubiquitinating Enzymes
  • Disease Progression
  • Female
  • Forkhead Box Protein M1 / genetics
  • Forkhead Box Protein M1 / metabolism*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Kaplan-Meier Estimate
  • Middle Aged
  • Ovarian Neoplasms / genetics
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Prognosis
  • Protein Binding
  • RNA Interference
  • Ubiquitination*

Substances

  • FOXM1 protein, human
  • Forkhead Box Protein M1
  • Deubiquitinating Enzymes
  • OTUB1 protein, human
  • Cysteine Endopeptidases