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Principal Investigator: CUN-YU WANG
Organization: UNIVERSITY OF CALIFORNIA LOS ANGELES
Fiscal Year: 2024
Award: $389,587
Funding agency: National Institute of Dental and Craniofacial Research
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.
Terms: <Acetylation><Amino Acid Motifs><Assay><B lymphoma Mo MLV insertion><BET bromodomain inhibitor><BET inhibitor><BETi><BMI1><BMI1 gene><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biological Assay><Body Tissues><Breast Cancer><Bromodomain><Bromodomain and Extra-Terminal motif inhibitor><Bromodomains and extra-terminal domain inhibitor><Buccal Cavity><Buccal Cavity Head and Neck><Cancer Genes><Cancer Treatment><Cancer-Promoting Gene><Cancers><Cavitas Oris><Cell Body><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Cervical Lymph Node><Cervical lymph node group><ChIP Sequencing><ChIP-seq><ChIPseq><Chemoresistance><Colorectal Cancer><Combination Drug Therapy><Common Neoplasm><Common Tumor><Complex><Cyclin-Dependent Kinases><Cyclin-Dependent Protein Kinases><DNA-Dependent RNA Polymerase II><Development><Enhancers><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Exhibits><Family member><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomic Segment><Genomics><Growth><HNSCC><Head and Neck><Head and Neck Cancer><Head and Neck Carcinoma><Head and Neck Squamous Cell Carcinoma><Head and neck structure><Histone Acetylation><Histone H3><Histone H4><Human><Impairment><Individual><Invaded><L-Lysine><Lysine><Malignant Breast Neoplasm><Malignant Cell><Malignant Head and Neck Neoplasm><Malignant Neck Neoplasm><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Mediator><Metabolic Protein Degradation><Metastasis><Metastasis to Lymph Nodes><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to Lymph Nodes><Metastatic Tumor><Metastatic Tumor to Lymph Nodes><Michigan><Modern Man><Molecular><Molecular Interaction><Mouth><Mutation><Neck><Neck Cancer><Neoplasm Metastasis><Neurofibrillary Tangles><Nitroquinolines><Oncogenes><Oncogenic><Oral cavity><Oropharyngeal><Oropharynx><Oropharynxs><Oxides><PDX model><Patient derived xenograft><Patients><Play><Polychemotherapy><Prognosis><Protein Family><Protein Motifs><Protein Turnover><Proteins><RNA Expression><RNA Polymerase B><RNA Polymerase II><RNA Seq><RNA sequencing><RNAseq><Reader><Regulatory Protein Degradation><Relapse><Resistance><Resistance development><Resistant development><Role><SCCHN><Secondary Neoplasm><Secondary Tumor><Stem Cell like><Subgroup><Survival Rate><Testing><Tissue Growth><Tissues><Transcript><Transcription><Transcription Activation><Transcription Activator><Transcription Coactivator><Transcription Elongation><Transcription Factor Coactivator><Transcription Factor Proto-Oncogene><Transcription Initiation><Transcription Regulation><Transcription factor genes><Transcriptional Activation><Transcriptional Activator><Transcriptional Activator/Coactivator><Transcriptional Coactivator><Transcriptional Control><Transcriptional Regulation><Transforming Genes><Tumor Cell Invasion><Tumor Invasion><Tumor Promotion><Universities><anti-cancer therapy><bromodomain extra-terminal inhibitor><cancer cell><cancer metastasis><cancer progenitor><cancer progenitor cells><cancer stem cell><cancer therapy><cancer-directed therapy><cdk Proteins><cell sorting><chemoresistant><chemotherapy resistance><chemotherapy resistant><chromatin immunoprecipitation-sequencing><cofactor><combination chemotherapy><combination pharmacotherapy><developing resistance><developmental><effective therapy><effective treatment><epigenetically><genetic approach><genetic strategy><genome mutation><genome segment><genomic region><head and neck squamous carcinoma><head and neck squamous cell cancer><head/neck cancer><improved><in vivo><inhibitor><lymph node metastasis><malignancy><malignant breast tumor><malignant head and neck tumor><malignant neck tumor><malignant progenitor><malignant stem cell><mouse model><murine model><neoplasm/cancer><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ontogeny><oral pharyngeal><patient derived xenograft model><prevent><preventing><protein degradation><recruit><resistant><self-renew><self-renewal><social role><stem cell characteristics><stemness><tangle><therapeutic target><transcription co-activator><transcription factor><transcriptional co-activator><transcriptome sequencing><transcriptomic sequencing><treatment strategy><tumor><tumor cell metastasis><tumor growth><tumorigenic>