Targeting Super-Enhancers Suppresses Cancer Stemness and Invasion of HNSCC

靶向超级增强剂抑制癌症干细胞和 HNSCC 的侵袭

基本信息

批准号：
10404040
负责人：
CUN-YU WANG
金额：
$ 39.36万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10404040
关键词：
Amino Acid Motifs BMI1 gene Binding Biological Assay Bromodomain Cells Cervical lymph node group ChIP-seq Chemoresistance Colorectal Cancer Combination Drug Therapy Common Neoplasm Complex Cyclin-Dependent Kinases DNA Polymerase II DNA-Directed RNA Polymerase Development Enhancers Epigenetic Process Exhibits Family member Gene Expression Gene Targeting Genes Genetic Transcription Genomic Segment Genomics Growth Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Head and neck structure Histone H3 Histone H4 Histones Human Impairment Individual Lead Lysine Malignant Epithelial Cell Malignant Neoplasms Mediator of activation protein Metastatic Neoplasm to Lymph Nodes Michigan Molecular Mutation Neck Cancer Neoplasm Metastasis Neurofibrillary Tangles Nitroquinolines Oncogenes Oncogenic Oral cavity Oropharyngeal Oxides Patients Play Prognosis Protein Family Proteins Reader Relapse Resistance Resistance development Role Subgroup Survival Rate Testing Tissues Transcript Transcription Elongation Transcription Initiation Transcriptional Activation Transcriptional Regulation Tumor Cell Invasion Universities base cancer cell cancer stem cell cancer therapy cofactor effective therapy genetic approach improved in vivo inhibitor malignant breast neoplasm mouse model novel novel strategies novel therapeutic intervention novel therapeutics patient derived xenograft model prevent protein degradation recruit self-renewal stemness therapeutic target transcription factor transcriptome sequencing treatment strategy tumor tumor growth tumorigenic

项目摘要

The long-term objectives of this application are to understand how super-enhancers (SEs) control the invasive growth and metastasis of head and neck squamous cell carcinoma (HNSCC) and to develop novel therapeutics for HNSCC. HNSCC is highly invasive and resistant to cancer therapy and frequently metastasizes to cervical lymph node, and patients with HNSCC have poor prognosis compared to other cancers such as breast and colorectal cancers. Therefore, novel effective therapies need to be developed for HNSCC patients. SEs are a genomic region that consists of multiple enhancers which are collectively bound by a set of transcription factors and epigenetic readers to drive transcription of genes associated with cell identity. Bromodomain-containing protein 4 (BRD4) is one of the four bromodomain and extra-terminal motif (BET) protein family members. In SEs, BRD4 functions as an epigenetic reader that recognizes and interacts with acetylated lysine residues on histone H3 and H4. Upon binding to the acetylated histones, BRD4 recruits the Mediator complex, the cyclin-dependent kinase 7 (CDK7) complex, and other factors to facilitate transcription initiation and elongation. Growing evidence suggests that SEs preferentially regulated the transcription of key oncogenes in various cancers which can be selectively inhibited by BET inhibitors (BETi). To explore whether SEs are a therapeutic target for HNSCC, we performed preliminary studies to characterize SEs in HNSCC, and discovered that SEs selectively controlled the transcription of a set of oncogenic genes associated with cancer stemness and invasion in addition to some common tumor-promoting genes. Using the newly-established mouse model of HNSCC that allows us to trace cancer stem cells (CSCs) in vivo, we found that disruption of SEs by BETi could potently eliminate CSCs and inhibit HNSCC invasive growth in vivo. We also showed that the new BET degrader (BETd) potently inhibited the expression of cancer stemness and pro-invasive genes by inducing BET family protein degradation. Based on these exciting preliminary studies, in this application, we hypothesize that SEs control the expression of cancer stemness and pro-invasive genes, and targeting SEs by BETd might help to eliminate CSCs and block tumor cell invasion, thereby improving anti-tumor efficacy and preventing lymph node metastasis of HNSCC. To test our hypothesis, we propose the following three specific aims: 1) Determine whether disruption of SEs suppresses tumor invasive growth and metastasis and effectively eliminates CSCs in a mouse model of HNSCC; 2) Determine whether the disruption of SEs inhibits the self-renewal, tumorigenic potentials and metastasis of CSCs isolated from human HNSCC; and 3) Determine how SEs are assembled in HNSCC and explore the molecular mechanisms by which disruption of SEs inhibits cancer stemness and invasion of HNSCC. Novel findings from our studies may lead to the development of novel strategies for the treatment of human HNSCC.

该应用程序的长期目标是了解超级增强器 (SE) 如何控制头颈鳞状细胞癌（HNSCC）的侵袭性生长和转移，并开发新的 HNSCC 的治疗。 HNSCC 具有高度侵袭性，对癌症治疗有抵抗力，并且经常发生转移与颈部淋巴结相比，HNSCC 患者的预后较差，例如乳腺癌和结直肠癌。因此，需要为 HNSCC 患者开发新的有效疗法。 SE 是由多个增强子组成的基因组区域，这些增强子共同由一组增强子结合在一起转录因子和表观遗传阅读器驱动与细胞身份相关的基因转录。含溴结构域蛋白 4 (BRD4) 是四个溴结构域和额外末端基序 (BET) 之一蛋白质家族成员。在 SE 中，BRD4 充当表观遗传阅读器，识别并相互作用组蛋白 H3 和 H4 上的乙酰化赖氨酸残基。与乙酰化组蛋白结合后，BRD4 招募介体复合体、细胞周期蛋白依赖性激酶 7 (CDK7) 复合体和其他促进转录的因子引发和伸长。越来越多的证据表明 SE 优先调控关键基因的转录 BET抑制剂（BETi）可以选择性抑制各种癌症中的癌基因。探讨是否 SE 是 HNSCC 的治疗靶点，我们进行了初步研究来描述 HNSCC 中 SE 的特征，并且发现 SE 选择性地控制一组与癌症相关的致癌基因的转录除了一些常见的促肿瘤基因之外，还包括干性和侵袭性。利用新成立的 HNSCC 小鼠模型使我们能够在体内追踪癌症干细胞 (CSC)，我们发现 SE 的破坏 BETi 可以有效消除 CSC 并抑制 HNSCC 体内侵袭性生长。我们还表明，新的 BET 降解剂 (BETd) 通过诱导癌症干细胞和促侵袭基因的表达，有效抑制 BET 家族蛋白质降解。基于这些令人兴奋的初步研究，在本应用中，我们假设 SE 控制癌症干性和促侵袭基因的表达，通过 BETd 靶向 SE 可能有助于消除CSC并阻止肿瘤细胞侵袭，从而提高抗肿瘤功效并预防 HNSCC 淋巴结转移。为了检验我们的假设，我们提出以下三个具体目标：1）确定 SE 的破坏是否能有效抑制肿瘤侵袭性生长和转移消除 HNSCC 小鼠模型中的 CSC； 2) 确定 SE 的破坏是否会抑制从人类 HNSCC 中分离的 CSC 的自我更新、致瘤潜力和转移； 3) 确定 SEs 如何在 HNSCC 中组装并探索 SEs 破坏抑制的分子机制 HNSCC 的癌症干细胞和侵袭。我们研究的新发现可能会导致新的开发治疗人类 HNSCC 的策略。