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Understanding the role of an aberrant hepatic nuclear transcription circuit in prostate cancer tumorigenesis and castration resistance

了解异常肝核转录回路在前列腺癌肿瘤发生和去势抵抗中的作用

基本信息

批准号：
10224110
负责人：
Yu Chen
金额：
$ 49.96万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10224110
关键词：
3-Dimensional ATAC-seq Address Androgen Receptor Binding Binding Sites Biological Assay Biological Markers CHD1 gene Castration Cell Line Cell Lineage Cells ChIP-seq Chromatin Clinical Data Dependence Diagnostic Ectopic Expression Enhancers Family Fibroblasts Fibrous capsule of kidney Gastrointestinal tract structure Gene Expression Gene Expression Profile Genes Genetic Epistasis Genetic Recombination Genetic Transcription Genetically Engineered Mouse Growth HNF4A gene Hepatic Human In Vitro Individual Lead Ligands Light Maintenance Malignant neoplasm of prostate Maps Mediating Metastatic Prostate Cancer Modeling Molecular Mus Mutation Nuclear Nuclear Receptors Oncogenic Organ Organoids Patients Phenotype Physiological Prevalence Prostate Resistance Role Signal Transduction Time Tissues androgen sensitive biomarker development cancer initiation cell growth embryonic stem cell experimental study gastrointestinal genetic signature in vivo in vivo Model insight knock-down molecular modeling next generation novel novel marker programs prostate cancer cell prostate cancer model prostate carcinogenesis response targeted treatment therapeutic target therapy resistant transcription factor transcriptome tumor tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY/ABSTRACT The discovery of ERG fusions in prostate cancer has set a paradigm where aberrant expression of non- mutated transcription factors at levels that are physiologic in other tissues can drive oncogenesis. We have uncovered that a subset of prostate cancers aberrantly express a gene signature normally restricted to the gastrointestinal (GI) tract and we call this the PCa-GI signature. The prevalence of this phenotype jumps from ~8% of primary prostate cancer to 30% of castration-resistance metastatic prostate cancer. Our data indicates that these GI genes are coordinately regulated by hepatic nuclear factor 1α (HNF1A) and hepatic nuclear factor 4γ (HNF4G). These two transcription factor families (HNF1 and HNF4), together with any FOXA-family transcription factor, have been well characterized to form a core autoregulatory loop to govern the GI lineage specification and can reprogram fibroblasts into the GI lineage, similar to the “Yamanaka factors” in governing the embryonic stem cell lineage. Prostate lineage express high endogenous levels of FOXA1. Our preliminary data using the 22Rv1 cell line that express the PCa-GI signature indicates that the HNF1A/HNF4G transcription circuit is required both to maintain expression of GI specific genes and for growth of HNF1A/HNF4G-positive prostate cancer cells. Further, ectopic expression of HNF4G in HNF1A/HNF4G- negative prostate cancer cells turns on the PCa-GI signature and leads to more rapid progression to castration-resistance. ChIP-seq studies show that HNF4G is necessary and sufficient to maintain GI lineage- specific enhancers, implying that HNF4G is a “pioneer” transcription factor that can bind to closed chromatin to establish novel enhancers in the prostate lineage. The overall objective of our proposal is to understand the mechanistic role of the aberrant expression of HNF1A and HNF4G in prostate cancer tumorigenesis and progression to castration resistance. We will utilize next-generation patient-derived prostate cancer organoid models that are molecularly and clinical well annotated to define the broad requirement of the HNF1A/HNF4G circuit in tumors that aberrantly activates the PCa-GI signature. To understand their role in tumorigenesis, we will model ectopic HNF1A or HNF4G expression in a mouse prostate organoids isolated from genetically engineered mice with different combinations of SPOPF133V mutation, Chd1 loss, and Pten loss. To study their role in castration-resistance, we will dissect their interaction with AR-dependent transcriptome in both in vitro and in vivo models. We will further correlate gene expression with cistrome and chromatin landscape studies. If successful, our studies will define a novel mechanism of prostate cancer tumorigenesis and castration resistance. HNF1A/HNF4G can be developed as biomarkers. Furthermore, because HNF4G is a ligand dependent nuclear transcription factor, this subset of prostate cancer can potentially be therapeutically targeted.

项目总结/文摘