USP36 promotes tumorigenesis and tamoxifen resistance in breast cancer by deubiquitinating and stabilizing ERα.

IF 11.4 1区 医学 Q1 ONCOLOGY
Ting Zhuang, Shuqing Zhang, Dongyi Liu, Zhongbo Li, Xin Li, Jiaoyan Li, Penghe Yang, Chenmiao Zhang, Jiayao Cui, Mingxi Fu, Fangyu Shen, Lei Yuan, Zhao Zhang, Peng Su, Jian Zhu, Huijie Yang
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引用次数: 0

Abstract

Background: Breast 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.

Methods: We 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.

Results: In 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.

Conclusion: Our study revealed the possibility that inhibiting USP36 combined with tamoxifen could provide a potential therapy for breast cancer.

USP36 通过去泛素化和稳定 ERα 促进乳腺癌的肿瘤发生和他莫昔芬抗性。
背景:乳腺癌是全球女性发病率最高的癌症。过度激活的雌激素受体(ER)α信号被认为是腔内乳腺癌的主要因素,它可以通过他莫昔芬等选择性雌激素受体调节剂(SERM)得到有效控制。然而,约有 30%-40% 的 ER + 乳腺癌病例在他莫昔芬治疗后会复发。这意味着乳腺癌的治疗仍然受到他莫昔芬耐药性的阻碍。最近的研究表明,ERα的翻译后修饰在内分泌抵抗中起着重要作用。ERα蛋白及其转录组的稳定性受E3泛素连接酶和去泛素酶之间的平衡调节。据目前所知,人类基因组中编码了约100种去泛素化酶,但仍不清楚哪些去泛素化酶在雌激素信号转导和内分泌抗性中发挥关键作用。因此,解码对雌激素信号转导(包括对ERα表达和稳定性的控制)有重要影响的关键泛素化酶,对于改善乳腺癌治疗至关重要:方法:我们使用了几种ER阳性乳腺癌细胞系、DUB siRNA文库筛选、异种移植模型、内分泌耐药(ERα-Y537S)模型,并进行了免疫印迹、实时PCR、RNA测序、免疫荧光和荧光素酶活性测定,以研究USP36在乳腺癌进展和他莫昔芬耐药中的功能:本研究通过去泛素酶 siRNA 文库筛选,发现泛素特异性肽酶 36(USP36)是参与 ERα 信号转导和乳腺癌进展的关键去泛素酶。体外和体内研究表明,USP36(而非其催化无活性突变体(C131A))可通过ERα信号转导促进乳腺癌的进展。相反,沉默 USP36 则会抑制肿瘤发生。在对内分泌治疗耐药的模型中,沉默 USP36 会破坏 ERα 的耐药形式(Y537S)的稳定性,并恢复对他莫昔芬的敏感性。分子研究表明,USP36 抑制了与 K48 链接的 ERα 多泛素化,并增强了 ERα 的转录组。值得注意的是,我们的研究结果表明 USP36 是治疗乳腺癌的新型生物标记物:我们的研究揭示了抑制 USP36 与他莫昔芬联用可为乳腺癌提供一种潜在疗法的可能性。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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