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: 10618847
• 负责人: CUN-YU WANG
• 金额: $ 39.75万
• 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/10618847
• 关键词: Acetylation; Amino Acid Motifs; BMI1 gene; Binding; Biological Assay; Bromodomain; Bromodomains and extra-terminal domain inhibitor; Cell Separation; Cells; Cervical lymph node group; ChIP-seq; Chemoresistance; Colorectal Cancer; Combination Drug Therapy; Common Neoplasm; Complex; Cyclin-Dependent Kinases; Development; Enhancers; Epigenetic Process; Exhibits; Family member; Gene Expression; Genes; Genetic Transcription; Genomic Segment; Genomics; Growth; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Histone Acetylation; Histone H3; Histone H4; Human; Impairment; Individual; Invaded; Lysine; Malignant Neoplasms; Mediator; Metastatic Neoplasm to Lymph Nodes; Michigan; Molecular; Mutation; Neck; Neck Cancer; Neoplasm Metastasis; Neurofibrillary Tangles; Nitroquinolines; Oncogenes; Oncogenic; Oral cavity; Oropharyngeal; Oxides; Patients; Play; Prognosis; Protein Family; Proteins; RNA Polymerase II; Reader; Relapse; Resistance; Resistance development; Role; Subgroup; Survival Rate; Testing; Tissues; Transcript; Transcription Coactivator; Transcription Elongation; Transcription Initiation; Transcriptional Activation; Transcriptional Regulation; Tumor Cell Invasion; Tumor Promotion; Universities; 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.

本申请的长期目标是了解超级增强子（SE）如何控制细胞内的细胞凋亡。 头颈部鳞状细胞癌（HNSCC）侵袭性生长和转移，并开发新的 HNSCC的治疗方法。HNSCC具有高度侵袭性，对癌症治疗具有抗性，并且经常转移 与其他癌症相比，HNSCC患者的预后较差， 乳腺癌和结肠直肠癌。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，所述多个增强子被一组 转录因子和表观遗传阅读器来驱动与细胞身份相关的基因转录。 含溴结构域蛋白4（Bromodomain-containing protein 4，BRD 4）是四个溴结构域和末端外基序（BET）之一。 蛋白质家族成员。在SE中，BRD 4作为表观遗传阅读器发挥作用， 组蛋白H3和H4上的乙酰化赖氨酸残基。在与乙酰化组蛋白结合后，BRD 4募集乙酰化组蛋白， 介体复合物、细胞周期蛋白依赖性激酶7（CDK 7）复合物和其他促进转录的因子 引发和延伸。越来越多的证据表明，SE优先调节关键基因的转录， 在各种癌症中的癌基因，其可以被BET抑制剂（BETi）选择性抑制。探讨是否 SE是HNSCC的治疗靶点，我们进行了初步研究以表征HNSCC中的SE， 发现SE选择性地控制一组与癌症相关的致癌基因的转录 干细胞性和侵袭性以及一些常见的促肿瘤基因。利用新成立的 HNSCC的小鼠模型允许我们在体内追踪癌症干细胞（CSC），我们发现SE的破坏 BETi能有效清除CSCs，抑制HNSCC的侵袭性生长。我们还发现， BET降解剂（BETd）通过诱导肿瘤细胞增殖， BET家族蛋白降解。基于这些令人兴奋的初步研究，在本申请中，我们假设 SEs控制癌干性和促侵袭基因的表达，通过BETd靶向SEs可能 有助于清除肿瘤干细胞，阻断肿瘤细胞侵袭，从而提高抗肿瘤疗效， HNSCC淋巴结转移。为了验证我们的假设，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的破坏是否抑制HNSCC小鼠模型中的CSC; 从人HNSCC分离的CSC的自我更新、致瘤潜力和转移;以及3）确定 SEs是如何在HNSCC中组装的，并探索SEs的破坏抑制HNSCC的分子机制。 癌的干性和侵袭性。我们研究中的新发现可能会导致小说的发展 治疗人类HNSCC的策略。