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.

该应用程序的长期目标是了解超级增强子（se）如何控制细胞的生长