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Molecular Cancer Research
Molecular Cancer Research
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Cancer “-omics”

Single-Cell Transcriptomics Analysis Identifies Nuclear Protein 1 as a Regulator of Docetaxel Resistance in Prostate Cancer Cells

Patricia M. Schnepp, Greg Shelley, Jinlu Dai, Nicole Wakim, Hui Jiang, Atsushi Mizokami and Evan T. Keller
Patricia M. Schnepp
1Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan.
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Greg Shelley
1Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan.
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Jinlu Dai
1Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan.
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Nicole Wakim
2Department of Biostatics, University of Michigan, Ann Arbor, Michigan.
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  • ORCID record for Nicole Wakim
Hui Jiang
2Department of Biostatics, University of Michigan, Ann Arbor, Michigan.
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Atsushi Mizokami
3Department of Urology, Kanazawa University, Kanazawa, Ishikawa, Japan.
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Evan T. Keller
1Department of Urology, University of Michigan Medical School, Ann Arbor, Michigan.
4Biointerfaces Institute, University of Michigan Medical School, Ann Arbor, Michigan.
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  • For correspondence: etkeller@umich.edu
DOI: 10.1158/1541-7786.MCR-20-0051 Published September 2020
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Abstract

The majority of patients with prostate cancer treated with docetaxel develop resistance to it. To better understand the mechanism behind the acquisition of resistance, we conducted single-cell RNA-sequencing (scRNA-seq) of docetaxel-sensitive and -resistant variants of DU145 and PC3 prostate cancer cell lines. Overall, sensitive and resistant cells clustered separately. Differential gene expression analysis between resistant and sensitive cells revealed 182 differentially expressed genes common to both prostate cancer cell lines. A subset of these genes gave a gene expression profile in the resistant transcriptome-like–sensitive cells similar to the resistant cells. Exploration for functional gene pathways identified 218 common pathways between the two cell lines. Protein ubiquitination was the most differentially regulated pathway and was enriched in the resistant cells. Transcriptional regulator analysis identified 321 potential regulators across both cell lines. One of the top regulators identified was nuclear protein 1 (NUPR1). In contrast to the single-cell analysis, bulk analysis of the cells did not reveal NUPR1 as a promising candidate. Knockdown and overexpression of NUPR1 in the prostate cancer cells demonstrated that NUPR1 confers docetaxel resistance in both cell lines. Collectively, these data demonstrate the utility of scRNA-seq to identify regulators of drug resistance. Furthermore, NUPR1 was identified as a mediator of prostate cancer drug resistance, which provides the rationale to explore NUPR1 and its target genes for reversal of docetaxel resistance.

Implications: Using single-cell sequencing of prostate cancer, we show that NUPR1 plays a role in docetaxel resistance.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2020;18:1290–301

  • Received January 14, 2020.
  • Revision received April 1, 2020.
  • Accepted June 3, 2020.
  • Published first June 8, 2020.
  • ©2020 American Association for Cancer Research.
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Molecular Cancer Research: 18 (9)
September 2020
Volume 18, Issue 9
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Single-Cell Transcriptomics Analysis Identifies Nuclear Protein 1 as a Regulator of Docetaxel Resistance in Prostate Cancer Cells
Patricia M. Schnepp, Greg Shelley, Jinlu Dai, Nicole Wakim, Hui Jiang, Atsushi Mizokami and Evan T. Keller
Mol Cancer Res September 1 2020 (18) (9) 1290-1301; DOI: 10.1158/1541-7786.MCR-20-0051

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Single-Cell Transcriptomics Analysis Identifies Nuclear Protein 1 as a Regulator of Docetaxel Resistance in Prostate Cancer Cells
Patricia M. Schnepp, Greg Shelley, Jinlu Dai, Nicole Wakim, Hui Jiang, Atsushi Mizokami and Evan T. Keller
Mol Cancer Res September 1 2020 (18) (9) 1290-1301; DOI: 10.1158/1541-7786.MCR-20-0051
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