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.

项目概要/摘要前列腺癌中 ERG 融合的发现树立了一个范例，其中非其他组织中生理水平的突变转录因子可以驱动肿瘤发生。发现前列腺癌的一个子集异常表达通常局限于胃肠 (GI) 道，我们称之为 PCa-GI 特征。这种表型的流行程度从我们的数据表明，约 8% 的原发性前列腺癌和 30% 的去势抵抗性转移性前列腺癌。这些GI基因受到肝核因子1α（HNF1A）和肝核因子的协调调节因子 4γ (HNF4G) 这两个转录因子家族（HNF1 和 HNF4）以及任何 FOXA 家族。转录因子，已被充分表征以形成核心自动调节环来控制胃肠道谱系规范并可以将成纤维细胞重新编程为胃肠道谱系，类似于控制中的“山中因素” 胚胎干细胞谱系表达高内源水平的 FOXA1。我们使用表达 PCa-GI 特征的 22Rv1 细胞系的初步数据表明 HNF1A/HNF4G 转录电路对于维持胃肠道特定基因的表达和生长都是必需的 HNF1A/HNF4G 阳性前列腺癌细胞的 HNF1A/HNF4G 异位表达。阴性前列腺癌细胞开启 PCa-GI 信号并导致更快地进展为 ChIP-seq 研究表明 HNF4G 对于维持 GI 谱系是必要且充分的。特异性增强子，这意味着 HNF4G 是一种“先锋”转录因子，可以与封闭染色质结合在前列腺谱系中建立新的增强子。我们提案的总体目标是了解异常表达的机制作用我们将利用 HNF1A 和 HNF4G 在前列腺癌肿瘤发生和进展为去势抵抗中的作用。分子和临床表现良好的下一代患者来源的前列腺癌类器官模型注释定义了异常激活肿瘤中 HNF1A/HNF4G 回路的广泛要求为了了解它们在肿瘤发生中的作用，我们将对异位 HNF1A 或 HNF4G 进行建模。从基因工程小鼠中分离出的小鼠前列腺类器官中的表达 SPOPF133V 突变、Chd1 缺失和 Pten 缺失的组合为了研究它们在去势抵抗中的作用。我们将在体外和体内模型中进一步剖析它们与 AR 依赖性转录组的相互作用。如果成功，我们的研究将确定基因表达与顺反子和染色质景观研究的相关性。前列腺癌肿瘤发生和去势抵抗的新机制可能是HNF1A/HNF4G。此外，由于 HNF4G 是一种配体依赖性核转录因子，前列腺癌的这一亚型有可能成为治疗目标。