Defining the epigenetic landscape in human prostate cancer

定义人类前列腺癌的表观遗传景观

基本信息

批准号：
9438502
负责人：
MYLES A BROWN
金额：
$ 60.08万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2020-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9438502
关键词：
Affect Androgen Receptor Androgen Suppression Androgens Atlases Automobile Driving Binding Binding Sites Biological Biopsy Cancer Etiology Castration Cell Line Cells Cessation of life Clinical Complex DNA DNA Binding Dana-Farber Cancer Institute Data Data Quality Data Set Development Disease Disease Progression Disease Resistance Drug resistance Epigenetic Process Epithelial Cells Epithelium Experimental Models Freezing Gene Targeting Genes Genetic Goals High-Throughput Nucleotide Sequencing Human Investigation LNCaP Link Localized Disease Lymph Node Tissue Malignant Neoplasms Malignant neoplasm of prostate Maps Measures Metastatic Neoplasm to Lymph Nodes Metastatic to Modeling Neoplasm Metastasis Nuclear Pathway interactions Play Process Prostate Protocols documentation Reproducibility Research Infrastructure Resistance Sampling Signal Transduction Site Specimen Techniques Therapeutic Intervention Time Tissue Sample Tissues Transcriptional Regulation Tumor Tissue United States VCaP Work Xenograft Model androgen sensitive biomarker development cancer drug resistance chromatin immunoprecipitation clinically relevant disease natural history epigenome experimental study genome editing genome-wide human tissue innovation insight knock-down men new therapeutic target novel overexpression programs prostate cancer cell line prostate cancer progression prostate carcinogenesis public health relevance small hairpin RNA therapy development transcription factor transcriptome sequencing tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The androgen receptor (AR) is central to prostate cancer development, progression, and drug resistance. The AR is a nuclear transcription factor (TF) that binds to DNA and regulates gene activity. The set of genome-wide AR-DNA binding sites is termed the AR cistrome. A complex interplay between AR and its co-regulators determines the genes targeted for transcriptional regulation. Using newly developed techniques for AR chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in human prostate specimens, we unambiguously show that the AR program is highly dynamic and is determined, at least in part, by the presence of available co-regulators. In particular, the pioneer TF FOXA1 and the prostate lineage- specific TF HOXB13 appear to co-localize at tumor tissue-specific AR sites. The overall objectives of the present proposal are to characterize the mechanisms underlying AR reprogramming during tumorigenesis and - for the first time - to characterize the AR program in human tissue during progression from localized prostate cancer to metastatic, drug-resistant disease. In the first aim, ChIP-seq will be performed in cell line models for AR-expressing normal prostate epithelium (LHSAR) and prostate cancer (LNCaP and VCaP). Changes in the cistromes of AR, FOXA1 and HOXB13 will be measured as each TF is knocked down via shRNA and genome editing or overexpressed via lentiviral transduction. RNA-seq will also be performed for each cell line condition to determine the genes affected by epigenetic reprogramming. In the second and third aims, the epigenetic landscape of the AR will be systematically charted via ChIP-seq in human specimens: localized tissue, untreated metastatic tissue, castration-resistant metastases and enzalutamide-resistant disease. Completion of the novel experiments outlined in this proposal will provide an unparalleled look at how master transcription factors drive prostate cancer progression. Specifically, we will discover: (i) how the AR is reprogrammed during prostate cancer development and progression, and which co-regulators are facilitating this process, (ii) how the AR is reprogrammed during the acquisition of resistance to enzalutamide and, if so, which co-regulators are facilitating this process, and (iii) other non-AR master regulators that are driving prostate cancer progression. The proposed experiments will also enable us to identify the target genes that are affected by AR reprogramming. The project will result in an atlas of the epigenetic landscape as the disease progresses to the castration-resistant metastatic state, which is uniformly fatal. The genetic loci and target genes comprising this dataset will stimulate new targets for therapeutic intervention.

描述（通过应用证明）：雄激素最近（AR）是前列腺癌发展的核心和耐药性。地点被称为AR CISTROME。尤其是监管机构先锋TF FOXA1和前列腺谱系在肿瘤组织特异性的AR位置上启动。前列腺癌对毒药模型中的抗药性疾病（LHSAR）和前列腺癌（LNCAP）和VCAP进行。在第二和第三个目标中确定受表观遗传重编程的基因：局部组织，未处理的转移组织，castration抗性转移和抗性疾病。因素驱动前列腺癌的进展。 iii）其他非AR的监管机构也将靶向AR重新编程的基因数据集的靶基因组成将刺激治疗间隔的新目标。