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

• 批准号: 9753189
• 负责人: Yu Chen
• 金额: $ 48.17万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753189
• 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

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/摘要 前列腺癌中ERG融合的发现已经建立了一个范例，其中非- 在其他组织中处于生理水平的突变转录因子可驱动肿瘤发生。我们有 发现前列腺癌的一个子集异常表达一种基因签名，通常仅限于 胃肠道（GI），我们称之为PCa-GI签名。这种表型的流行率从 约8%的原发性前列腺癌至30%的去势抵抗性转移性前列腺癌。我们的数据表明 这些GI基因受肝核因子1α（HNF 1A）和肝细胞核因子1 α（HNF 1A）的协同调控， 因子4γ（HNF 4G）。这两个转录因子家族（HNF 1和HNF 4）与任何FOXA家族一起 转录因子，已被很好地表征，形成一个核心自动调节环，以控制GI谱系 规范，并可以重新编程成纤维细胞到GI谱系，类似于“山中因子”，在管理 胚胎干细胞谱系前列腺谱系表达高内源性水平的FOXA 1。 我们使用表达PCa-GI信号的22 Rv 1细胞系的初步数据表明， HNF 1A/HNF 4G转录回路是维持GI特异性基因表达和生长所必需的 HNF 1A/HNF 4G阳性前列腺癌细胞。此外，HNF 4G在HNF 1A/HNF 4G-1细胞中的异位表达， 阴性前列腺癌细胞开启PCa-GI信号，导致更快的进展， 去势抵抗ChIP-seq研究表明，HNF 4G是维持GI谱系的必要和充分条件。 特异性增强子，这意味着HNF 4G是一个“先锋”转录因子，可以结合封闭的染色质， 在前列腺谱系中建立新的增强子。 我们的建议的总体目标是了解异常表达的机械作用， HNF 1A和HNF 4G在前列腺癌肿瘤发生和去势抵抗进展中的作用我们将利用 下一代患者来源的前列腺癌类器官模型，在分子和临床上都很好 注释以定义肿瘤中异常激活HNF 1A/HNF 4G回路的广泛需求。 前列腺素-胃肠道标志为了了解它们在肿瘤发生中的作用，我们将异位HNF 1A或HNF 4G 在分离自具有不同基因工程小鼠的小鼠前列腺类器官中的表达 SPOPF 133 V突变、Chd 1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剖析它们与AR依赖性转录组的相互作用。我们将进一步 将基因表达与顺式组和染色质景观研究相关联。如果成功，我们的研究将确定 前列腺癌肿瘤发生和去势抵抗的新机制。HNF 1A/HNF 4G可以是 作为生物标志物。此外，由于HNF 4G是配体依赖性核转录因子， 前列腺癌的这一亚类可以潜在地作为治疗靶点。