Title: FOXM1 Deubiquitination by USP21 Regulates Cell Cycle Progression and Paclitaxel Sensitivity in Basal-like Breast Cancer.

Authors: Arceci, Anthony; Bonacci, Thomas; Wang, Xianxi; Stewart, Kyle; Damrauer, Jeffrey S; Hoadley, Katherine A; Emanuele, Michael J

Published In Cell Rep, (2019 03 12)

Abstract: The transcription factor FOXM1 contributes to cell cycle progression and is significantly upregulated in basal-like breast cancer (BLBC). Despite its importance in normal and cancer cell cycles, we lack a complete understanding of mechanisms that regulate FOXM1. We identified USP21 in an RNAi-based screen for deubiquitinases that control FOXM1 abundance. USP21 increases the stability of FOXM1, and USP21 binds and deubiquitinates FOXM1 in vivo and in vitro, indicating a direct enzyme-substrate relationship. Depleting USP21 downregulates the FOXM1 transcriptional network and causes a significant delay in cell cycle progression. Significantly, USP21 depletion sensitized BLBC cell lines and mouse xenograft tumors to paclitaxel, an anti-mitotic, frontline therapy in BLBC treatment. USP21 is the most frequently amplified deubiquitinase in BLBC patient tumors, and its amplification co-occurs with the upregulation of FOXM1 protein. Altogether, these data suggest a role for USP21 in the proliferation and potentially treatment of FOXM1-high, USP21-high BLBC.

PubMed ID: 30865895

MeSH Terms: No MeSH terms associated with this publication