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The deubiquitinating enzyme USP1 modulates ER? and modulates breast cancer progression.

ABSTRACT: Breast cancer is one of the most common malignancies worldwide, while the luminal types (ER? positive) accounts for two third of all breast cancer cases. Although ER? positive breast cancer could be effective controlled by endocrine therapy, most of the patients will develop endocrine resistance, which becomes a headache clinical issue for breast cancer field. Endocrine resistance could be caused by multiple pathway disorders, the dys-regulation of ER? signaling might be a critical factor, which makes it urgent and important to reveal the potential molecular mechanism of ER? signaling. In our current study, we identified a new deubiquitination enzyme USP1 through screening the whole DUB (Deubiquitinases) siRNA library. The expression of USP1 is elevated in human breast cancer compared with normal mammary tissues. Importantly, USP1 expression levels are specially correlated with poor survival in ER? positive patients. USP1 depletion inhibited breast cancer cell progression and ER? signaling activity. Immuno-precipitation assays indicate that USP1 associates with ER? and promotes its stability possibly via inhibiting ER? K48-linked poly-ubiquitination. In conclusion, our data implicate a non-genomic mechanism by USP1 via stabilizing ER? protein controls ER? target gene expression linked to breast cancer progression.

SUBMITTER: Niu Z

PROVIDER: S-EPMC7591989 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The deubiquitinating enzyme USP1 modulates ERα and modulates breast cancer progression.

Niu Zhiguo Z Li Xin X Feng Suyin S Huang Qingsong Q Zhuang Ting T Yan Cheng C Qian Hui H Ding Yinlu Y Zhu Jian J Xu Wenrong W

Journal of Cancer 20201012 23

Breast cancer is one of the most common malignancies worldwide, while the luminal types (ERα positive) accounts for two third of all breast cancer cases. Although ERα positive breast cancer could be effective controlled by endocrine therapy, most of the patients will develop endocrine resistance, which becomes a headache clinical issue for breast cancer field. Endocrine resistance could be caused by multiple pathway disorders, the dys-regulation of ERα signaling might be a critical factor, which ...[more]

PMID: 33123289

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Project description:BackgroundBreast cancer is the most prevalent cancer in women globally. Over-activated estrogen receptor (ER) α signaling is considered the main factor in luminal breast cancers, which can be effectively managed with selective estrogen receptor modulators (SERMs) like tamoxifen. However, approximately 30-40% of ER + breast cancer cases are recurrent after tamoxifen therapy. This implies that the treatment of breast cancer is still hindered by resistance to tamoxifen. Recent studies have suggested that post-translational modifications of ERα play a significant role in endocrine resistance. The stability of both ERα protein and its transcriptome is regulated by a balance between E3 ubiquitin ligases and deubiquitinases. According to the current knowledge, approximately 100 deubiquitinases are encoded in the human genome, but it remains unclear which deubiquitinases play a critical role in estrogen signaling and endocrine resistance. Thus, decoding the key deubiquitinases that significantly impact estrogen signaling, including the control of ERα expression and stability, is critical for the improvement of breast cancer therapeutics.MethodsWe used several ER positive breast cancer cell lines, DUB siRNA library screening, xenograft models, endocrine-resistant (ERα-Y537S) model and performed immunoblotting, real time PCR, RNA sequencing, immunofluorescence, and luciferase activity assay to investigate the function of USP36 in breast cancer progression and tamoxifen resistance.ResultsIn this study, we identify Ubiquitin-specific peptidase 36 (USP36) as a key deubiquitinase involved in ERα signaling and the advancement of breast cancer by deubiquitinases siRNA library screening. In vitro and in vivo studies showed that USP36, but not its catalytically inactive mutant (C131A), could promote breast cancer progression through ERα signaling. Conversely, silencing USP36 inhibited tumorigenesis. In models resistant to endocrine therapy, silencing USP36 destabilized the resistant form of ERα (Y537S) and restored sensitivity to tamoxifen. Molecular studies indicated that USP36 inhibited K48-linked polyubiquitination of ERα and enhanced the ERα transcriptome. It is interesting to note that our results suggest USP36 as a novel biomarker for treatment of breast cancer.ConclusionOur study revealed the possibility that inhibiting USP36 combined with tamoxifen could provide a potential therapy for breast cancer.

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The deubiquitinating enzyme USP1 modulates ER? and modulates breast cancer progression.

Publications

The deubiquitinating enzyme USP1 modulates ERα and modulates breast cancer progression.

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