Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer

Xiaohong Xia, Yuning Liao, Zhiqiang Guo, Yanling Li, Lili Jiang, Fangcheng Zhang, Chuyi Huang, Yuan Liu, Xuejun Wang, Ningning Liu, Jinbao Liu, Hongbiao Huang

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Estrogen receptor α (ERα) is expressed in ~67% of breast cancers and is critical to their proliferation and progression. The expression of ERα is regarded as a major prognostic marker, making it a meaningful target to treat breast cancer (BCa). However, hormone receptor-positive BCa was sometimes irresponsive or even resistant to classic anti-hormonal therapies (e.g., fulvestrant and tamoxifen). Hence, novel anti-endocrine therapies are urgent for ERα+ BCa. A phase II study suggested that bortezomib, an inhibitor blocking the activity of 20 S proteasomes, intervenes in cancer progression for anti-endocrine therapy in BCa. Here we report that proteasome-associated deubiquitinases (USP14 and UCHL5) inhibitors b-AP15 and platinum pyrithione (PtPT) induce growth inhibition in ERα+ BCa cells. Further studies show that these inhibitors induce cell cycle arrest and apoptosis associated with caspase activation, endoplasmic reticulum (ER) stress and the downregulation of ERα. Moreover, we suggest that b-AP15 and PtPT block ERα signaling via enhancing the ubiquitin-mediated degradation of ERα and inhibiting the transcription of ERα. Collectively, these findings demonstrate that proteasome-associated deubiquitinases inhibitors b-AP15 and PtPT may have the potential to treat BCa resistant to anti-hormonal therapy.

Original languageEnglish (US)
Article number75
JournalOncogenesis
Volume7
Issue number9
DOIs
StatePublished - Sep 1 2018

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Proteasome Endopeptidase Complex
Estrogen Receptors
Breast Neoplasms
Platinum
Endoplasmic Reticulum Stress
Deubiquitinating Enzymes
Tamoxifen
Therapeutics
Caspases
Ubiquitin
Cell Cycle Checkpoints
Down-Regulation
Hormones
Apoptosis
Growth
pyrithione

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer. / Xia, Xiaohong; Liao, Yuning; Guo, Zhiqiang; Li, Yanling; Jiang, Lili; Zhang, Fangcheng; Huang, Chuyi; Liu, Yuan; Wang, Xuejun; Liu, Ningning; Liu, Jinbao; Huang, Hongbiao.

In: Oncogenesis, Vol. 7, No. 9, 75, 01.09.2018.

Research output: Contribution to journalArticle

Xia, X, Liao, Y, Guo, Z, Li, Y, Jiang, L, Zhang, F, Huang, C, Liu, Y, Wang, X, Liu, N, Liu, J & Huang, H 2018, 'Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer', Oncogenesis, vol. 7, no. 9, 75. https://doi.org/10.1038/s41389-018-0086-y
Xia, Xiaohong ; Liao, Yuning ; Guo, Zhiqiang ; Li, Yanling ; Jiang, Lili ; Zhang, Fangcheng ; Huang, Chuyi ; Liu, Yuan ; Wang, Xuejun ; Liu, Ningning ; Liu, Jinbao ; Huang, Hongbiao. / Targeting proteasome-associated deubiquitinases as a novel strategy for the treatment of estrogen receptor-positive breast cancer. In: Oncogenesis. 2018 ; Vol. 7, No. 9.
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