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

• 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
• 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

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.

本应用程序的长期目标是了解超级增强剂（SES）如何控制 头部和颈部鳞状细胞癌（HNSCC）的侵入性生长和转移 HNSCC的治疗剂。 HNSCC具有高度侵入性，对癌症疗法具有抗药性，并且经常转移 与其他癌症（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。 SES是一个由多个增强子组成的基因组区域 转录因子和表观遗传读取器驱动与细胞身份相关的基因的转录。 含溴构域的蛋白4（BRD4）是四个溴结构域和末端基序之一（BET）之一 蛋白质家族成员。在SES中，BRD4充当表观遗传学读者，识别并与 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招募了 介体复合物，依赖细胞周期蛋白的激酶7（CDK7）复合物以及其他因素以促进转录 启动和伸长。越来越多的证据表明，SES优先调节了密钥的转录 在各种癌症中的癌基因，可以被BET抑制剂选择性抑制（BETI）。探索是否 SES是HNSCC的治疗靶标，我们进行了初步研究以表征HNSCC中的SES，并进行了初步研究。 发现SES选择性控制了与癌症相关的一组致癌基因的转录 除了一些常见的肿瘤基因外，干性和侵袭。使用新建立的 允许我们在体内追踪癌症干细胞（CSC）的HNSCC的小鼠模型，我们发现SES的破坏 BETI可以有效地消除CSC并抑制体内HNSCC侵入性生长。我们还表明了新的 BET DEGRADER（BETD）通过诱导，有效抑制癌症的表达和促侵入性基因 BET家族蛋白降解。基于这些令人兴奋的初步研究，在本应用中，我们假设 SES控制了癌症的表达和促侵入性基因，而BETD靶向SES可能 帮助消除CSC并阻止肿瘤细胞侵袭，从而提高抗肿瘤功效并防止 HNSCC的淋巴结转移。为了检验我们的假设，我们提出以下三个特定目的：1） 确定SES的破坏是否抑制肿瘤的侵入性生长和转移，并有效地 消除HNSCC小鼠模型中的CSC； 2）确定SES的破坏是否抑制 从人类HNSCC分离的CSC的自我更新，致瘤潜力和转移； 3）确定 如何在HNSCC中组装SE并探索SES抑制的分子机制 HNSCC的癌症和入侵。我们研究的新发现可能导致新颖的发展 治疗人类HNSCC的策略。