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

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

doi:10.1016/j.celrep.2019.02.054

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

Cell Rep. 2019 Mar 12;26(11):3076-3086.e6. doi: 10.1016/j.celrep.2019.02.054.

Authors

Anthony Arceci¹, Thomas Bonacci², Xianxi Wang², Kyle Stewart², Jeffrey S Damrauer³, Katherine A Hoadley³, Michael J Emanuele⁴

Affiliations

¹ Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
² Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
³ Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Genetics, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
⁴ Curriculum in Genetics and Molecular Biology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. Electronic address: emanuele@email.unc.edu.

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.

Keywords: breast cancer; cell cycle; chemotherapy; deubiquitinase; deubiquitination; gene regulation; transcription; ubiquitination.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents, Phytogenic / therapeutic use*
Cell Cycle*
Drug Resistance, Neoplasm*
Female
Forkhead Box Protein M1 / metabolism*
HEK293 Cells
HeLa Cells
Humans
MCF-7 Cells
Mammary Neoplasms, Experimental / drug therapy
Mammary Neoplasms, Experimental / metabolism*
Mice
Mice, Inbred BALB C
Mice, Nude
Paclitaxel / therapeutic use*
Ubiquitin Thiolesterase / metabolism
Ubiquitination*

Substances

Antineoplastic Agents, Phytogenic
Forkhead Box Protein M1
Foxm1 protein, mouse
Usp16 protein, mouse
Ubiquitin Thiolesterase
Paclitaxel

Abstract

Publication types

MeSH terms

Substances

Grants and funding