基本基因筛选确定含溴结构域蛋白 BRPF1 为内分泌治疗耐药乳腺癌的新靶点

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Annamaria Salvati, Giorgio Giurato, Jessica Lamberti, Ilaria Terenzi, Laura Crescenzo, Viola Melone, Luigi Palo, Alessandro Giordano, Francesco Sabbatino, Giuseppina Roscigno, Cristina Quintavalle, Gerolama Condorelli, Francesca Rizzo, Roberta Tarallo, Giovanni Nassa, Alessandro Weisz
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引用次数: 0

摘要

确定控制癌细胞增殖和存活的主表观遗传因素,有助于发现新的分子靶点,从而克服对现有药物疗法的耐药性。在乳腺癌(BC)中,对内分泌疗法(ET)的耐药性源于雌激素受体α(ERα)信号传导异常,其原因主要是遗传和表观遗传事件,目前仍不清楚。靶向雌激素受体α通路的关键上游成分为干扰癌细胞中的雌激素信号提供了一种独立于任何其他下游事件的方法。通过将全基因组 "退出 "筛选的计算分析与 siRNA 介导的基因敲除 (kd) 相结合,我们确定了一组管腔样、ERα + BC 中的重要基因,其中包括 BRPF1,它编码一种含溴结构域的蛋白,属于表观遗传阅读器家族,可作为染色质重塑器控制基因转录。为了从机理上深入了解BRPF1在BC和ERα信号转导中的作用,我们应用了染色质和转录组图谱分析、基因消减和靶向药理抑制以及细胞和功能测试。结果表明,BRPF1与ERα在BC细胞染色质上结合,阻断BRPF1可抑制细胞周期的进展,减少细胞增殖,并通过调节染色质的可及性介导转录组的变化。在抗雌激素(AE)敏感和耐受的 BC 细胞以及临床前患者衍生模型(PDOs)中,ERα 基因沉默导致的雌激素信号传导受到广泛抑制,从而产生了这种效应。BRPF1与ERα功能相互作用的特征揭示了雌激素反应性BC细胞存活的新调节因子,并表明这种表观遗传因子是治疗这些肿瘤的潜在新靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Essential gene screening identifies the bromodomain-containing protein BRPF1 as a new actionable target for endocrine therapy-resistant breast cancers
Identifying master epigenetic factors controlling proliferation and survival of cancer cells allows to discover new molecular targets exploitable to overcome resistance to current pharmacological regimens. In breast cancer (BC), resistance to endocrine therapy (ET) arises from aberrant Estrogen Receptor alpha (ERα) signaling caused by genetic and epigenetic events still mainly unknown. Targeting key upstream components of the ERα pathway provides a way to interfere with estrogen signaling in cancer cells independently from any other downstream event. By combining computational analysis of genome-wide ‘drop-out’ screenings with siRNA-mediated gene knock-down (kd), we identified a set of essential genes in luminal-like, ERα + BC that includes BRPF1, encoding a bromodomain-containing protein belonging to a family of epigenetic readers that act as chromatin remodelers to control gene transcription. To gather mechanistic insights into the role of BRPF1 in BC and ERα signaling, we applied chromatin and transcriptome profiling, gene ablation and targeted pharmacological inhibition coupled to cellular and functional assays. Results indicate that BRPF1 associates with ERα onto BC cell chromatin and its blockade inhibits cell cycle progression, reduces cell proliferation and mediates transcriptome changes through the modulation of chromatin accessibility. This effect is elicited by a widespread inhibition of estrogen signaling, consequent to ERα gene silencing, in antiestrogen (AE) -sensitive and -resistant BC cells and pre-clinical patient-derived models (PDOs). Characterization of the functional interplay of BRPF1 with ERα reveals a new regulator of estrogen-responsive BC cell survival and suggests that this epigenetic factor is a potential new target for treatment of these tumors.
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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