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.

项目摘要/摘要 在前列腺癌中发现ERG融合的发现已经树立了一个范式，非异常表达非 - 在其他组织中生理的水平上的突变转录因子可能会导致肿瘤发生。我们有 发现的一部分前列腺癌子集比异常表达了通常仅限于 胃肠道（GI）区，我们将其称为PCA-GI签名。这种表型的流行从 〜8％的原发性前列腺癌至30％的castration抗性转移性前列腺癌。我们的数据指示 这些GI基因由肝核因子1α（HNF1A）和肝核对协调调节 因子4γ（HNF4G）。这两个转录因子家族（HNF1和HNF4）以及任何FOXA家庭 转录因子已被很好地表征形成核心自动调节环以控制GI谱系 规格并可以将成纤维细胞重新编程为GI谱系，类似于管理中的“ Yamanaka因子” 胚胎干细胞谱系。前列腺谱系表达高内源性FOXA1。 我们使用表达PCA-GI签名的22RV1细胞系的初步数据表明 需要HNF1A/HNF4G转录电路，以维持GI特异性基因的表达和生长 HNF1A/HNF4G阳性前列腺癌细胞此外，HNF4G在HNF1A/HNF4G-中的生态表达 阴性前列腺癌细胞打开PCA-GI特征，并导致更快的进展到 cast割抗性。 CHIP-Seq研究表明，HNF4G是必要的，足以维持胃肠道谱。 特定增强剂，这意味着HNF4G是可以与封闭染色质结合的“先驱”转录因子 在前列腺谱系中建立新颖的增强剂。 我们提议的总体目的是了解异常表达的机械作用 前列腺癌肿瘤发生以及向cast割耐药性进展的HNF1A和HNF4G。我们将利用 下一代患者衍生的前列腺癌器官模型，它们是分子和临床井的 注释以定义肿瘤中HNF1A/HNF4G电路的广泛要求，该电路异常激活 PCA-GI签名。要了解它们在肿瘤发生中的作用，我们将建模生态HNF1A或HNF4G 从具有不同的基因工程小鼠分离的小鼠前列腺类器官中的表达 SPOPF133V突变，CHD1损失和PTEN损失的组合。为了研究它们在cast割抗性中的作用，我们 将在体外和体内模型中剖析其与AR依赖性转录组的相互作用。我们将进一步 将基因表达与Cistrome和染色质景观研究相关。如果成功，我们的研究将定义 前列腺癌肿瘤发生和cast割耐药性的新型机制。可以是HNF1A/HNF4G 作为生物标志物发展。此外，由于HNF4G是配体依赖的核转录因子，所以 这一子集的前列腺癌可能是治疗靶向的。