Inhibition of USP14 enhances the sensitivity of breast cancer to enzalutamide

Xiaohong Xia, Chuyi Huang, Yuning Liao, Yuan Liu, Jinchan He, Zhiqiang Guo, Lili Jiang, Xuejun Wang, Jinbao Liu, Hongbiao Huang

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Androgen receptor (AR) is expressed in approximately 70% of breast tumors. Recent studies increasingly support AR as a potential therapeutic target of AR-positive breast cancer. We have previously reported that deubiquitinase USP14 stabilizes AR proteins by deubiquitination and USP14 inhibition results in inhibition of cell growth and tumor progression in AR-positive prostate cancer and breast cancer. The current study aims to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with USP14 inhibition on breast cancer cells. Methods: The combining effects of enzalutamide and USP14 inhibition on breast cancer cell proliferation and apoptosis and associated cell signaling were evaluated in vitro and in vivo. Results: USP14 inhibition via administration of IU1 or USP14-specific siRNA/shRNA enhanced cell growth inhibition and apoptosis induction by enzalutamide in breast cancer cell lines in vitro and in vivo. Additionally, the combination of enzalutamide with USP14 inhibition/knockdown induced significant downregulation of AR proteins and suppression of AR-related signaling pathways, including Wnt/β-catenin and PI3K/AKT pathways. Moreover, AKT inhibition via MK2206 increased the antiproliferative and proapoptotic effects of enzalutamide+IU1 combined treatment. Conclusion: Collectively, our data suggest that USP14 inhibition in combination with enzalutamide represents a potentially new therapeutic strategy for breast cancer.

Original languageEnglish (US)
Article number220
JournalJournal of Experimental and Clinical Cancer Research
Volume38
Issue number1
DOIs
StatePublished - May 24 2019

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Androgen Receptors
Breast Neoplasms
Small Interfering RNA
Androgen Receptor Antagonists
Apoptosis
Catenins
Wnt Signaling Pathway
MDV 3100
Growth
Phosphatidylinositol 3-Kinases
Prostatic Neoplasms
Proteins
Down-Regulation
Cell Proliferation
Cell Line
Therapeutics
Neoplasms

Keywords

  • Androgen receptor
  • Breast cancer
  • Combination treatment
  • Enzalutamide
  • USP14

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Inhibition of USP14 enhances the sensitivity of breast cancer to enzalutamide. / Xia, Xiaohong; Huang, Chuyi; Liao, Yuning; Liu, Yuan; He, Jinchan; Guo, Zhiqiang; Jiang, Lili; Wang, Xuejun; Liu, Jinbao; Huang, Hongbiao.

In: Journal of Experimental and Clinical Cancer Research, Vol. 38, No. 1, 220, 24.05.2019.

Research output: Contribution to journalArticle

Xia, Xiaohong ; Huang, Chuyi ; Liao, Yuning ; Liu, Yuan ; He, Jinchan ; Guo, Zhiqiang ; Jiang, Lili ; Wang, Xuejun ; Liu, Jinbao ; Huang, Hongbiao. / Inhibition of USP14 enhances the sensitivity of breast cancer to enzalutamide. In: Journal of Experimental and Clinical Cancer Research. 2019 ; Vol. 38, No. 1.
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abstract = "Background: Androgen receptor (AR) is expressed in approximately 70{\%} of breast tumors. Recent studies increasingly support AR as a potential therapeutic target of AR-positive breast cancer. We have previously reported that deubiquitinase USP14 stabilizes AR proteins by deubiquitination and USP14 inhibition results in inhibition of cell growth and tumor progression in AR-positive prostate cancer and breast cancer. The current study aims to explore the anticancer effect of a treatment combining AR antagonist enzalutamide with USP14 inhibition on breast cancer cells. Methods: The combining effects of enzalutamide and USP14 inhibition on breast cancer cell proliferation and apoptosis and associated cell signaling were evaluated in vitro and in vivo. Results: USP14 inhibition via administration of IU1 or USP14-specific siRNA/shRNA enhanced cell growth inhibition and apoptosis induction by enzalutamide in breast cancer cell lines in vitro and in vivo. Additionally, the combination of enzalutamide with USP14 inhibition/knockdown induced significant downregulation of AR proteins and suppression of AR-related signaling pathways, including Wnt/β-catenin and PI3K/AKT pathways. Moreover, AKT inhibition via MK2206 increased the antiproliferative and proapoptotic effects of enzalutamide+IU1 combined treatment. Conclusion: Collectively, our data suggest that USP14 inhibition in combination with enzalutamide represents a potentially new therapeutic strategy for breast cancer.",
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