The role and mechanism of RNA m6A modification in the pathogenesis and drug-resistance of prostate cancer

RNA m6A修饰在前列腺癌发病及耐药中的作用及机制

基本信息

批准号：
10638634
负责人：
Jihoon Lee
金额：
$ 38.55万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10638634
关键词：
Address Adenosine Affect Androgen Receptor Androgens Binding Biological Assay Biological Process Cancer Patient Castration Cessation of life ChIP-seq Chromatin Clinical Complex Data Deposition Development Disease Drug resistance Enhancers Gene Expression Genetic Enhancer Element Genetic Transcription Goals Growth Hormones Human Link Malignant Neoplasms Malignant neoplasm of prostate Maps Mediating Messenger RNA Methylation Methyltransferase Modification Molecular Mutation Nitrogen Nuclear Oncogenic Pathogenesis Phase Phenotype Physical condensation Play Positioning Attribute Prostate Prostate Cancer therapy Proteins RNA RNA Splicing Reader Receptor Signaling Regulation Regulator Genes Relapse Reporting Resistance Role Signal Pathway Site-Directed Mutagenesis Testing Therapeutic Transactivation Transcriptional Activation Transcriptional Regulation Translations Treatment Failure United States Untranslated RNA Xenograft procedure abiraterone advanced prostate cancer androgen deprivation therapy antagonist cancer diagnosis cancer survival castration resistant prostate cancer drug relapse drug resistance development enzalutamide experimental study gain of function gene repression genome-wide human disease loss of function methylome mouse model novel therapeutic intervention patient derived xenograft model pharmacologic prostate cancer cell prostate cancer progression receptor binding receptor function receptor-mediated signaling transcriptome transcriptome sequencing tumor

项目摘要

PROJECT TITLE: The role and mechanism of RNA m6A modification in the pathogenesis and drug-resistance of prostate cancer PROJECT SUMMARY (ABSTRACT): Background: N6-methyladenosine (m6A) modification is the most prevalent and abundant internal modification in eukaryotic messenger RNAs (mRNAs) and plays diverse and important roles in normal biological processes. Emerging evidence suggest that m6A and m6A-assicated proteins also play critical roles in human diseases including cancers. Prostate cancer (PCa) is the most commonly diagnosed cancer with the second leading estimated deaths at the United States for more than a decade. Androgens and androgen receptor (AR) regulate normal growth and function of the prostate gland. However, aberrant regulation of androgens and AR signaling pathway are closely associated with PCa pathogenesis and progression. Thus, androgen deprivation therapies (ADT) or targeting AR function have always been the mainstay of therapeutic strategy against advanced prostate cancers. However, the current therapeutic strategies cannot cure most PCa patients due to drug resistance and relapse, and eventually develop metastatic, castration-resistant prostate cancer (mCRPC), a lethal stage of the disease. The acquired resistance to abiraterone and enzalutamide is considered as the main problem for the treatment failure and relapse of PCa. Therefore, it is crucial to elucidate the molecular mechanisms underlying PCa pathogenesis and drug resistance, which may contribute to the development of effective new therapeutic approaches to overcome the limitations of current treatment for PCa. RNA m6A modification is deposited by m6A methyltransferase complex composed of three core subunits METTL3, METTL14 and WTAP and may have functions as an important regulator of gene expression that can affect mRNA transcription, splicing, export, stability, and translation. Previously, we have reported that METTL3-catalyzed m6A modification of target mRNA plays critical oncogenic roles in human cancers including PCa, but its definitive roles in AR signaling activation and especially in drug-resistant AR signaling remain elusive. Our preliminary data imply that m6A modification on enhancer RNAs (eRNAs), which are regulatory RNAs transcribed from non-coding enhancer elements, may also have roles in drug resistance in PCa, which requires further systematic studies. The goal of this proposal is to prove the central hypothesis that METTL3-mediated RNA m6A modification plays essential roles in AR signaling, PCa pathogenesis and drug resistance. The m6A methylome of chromatin-associated regulator RNAs (carRNAs) and nascent RNAs will be mapped, analyzed and correlated with the genome-wide binding of AR and transcriptional machineries. Also, the role of YTHDC1, a nuclear m6A reader protein, will be systemically examined to investigate its relationship with the transactivation of AR and genome-wide distribution, as it has been known to regulate transcriptional activation or repression via binding to m6A-modified RNAs. Loss- and gain-of-function experiments will address the widespread impact of RNA m6A modification in controlling the activation of AR signaling and downstream gene expression, and thus will help uncover the molecular mechanism underlying the role of m6A modification in PCa pathogenesis. Finally, the effects of m6A modification manipulation in the AR signaling regulation with drug-resistant AR mutations will be explored using a xenograft PCa mouse model, as well as a patient-derived xenograft (PDX) models and a panel of assays will be placed to examine the underlying molecular mechanism. Our proposed study will successfully reveal the role of RNA m6A modification in AR signaling and PCa pathogenesis, and help evaluate the clinical potential pharmacological inhibition of m6A modification in PCa, especially metastatic and drug resistant PCa.

项目标题： RNA M6A修饰的作用和机制在前列腺癌的发病机理和抗药性中项目摘要（摘要）：背景：N6-甲基腺苷（M6A）修饰是最普遍，最丰富的内部修饰真核信使RNA（mRNA）在正常的生物学过程中扮演着多种多样的重要作用。新兴的证据表明，M6A和M6A鉴定蛋白在人类疾病中也起着关键作用包括癌症。前列腺癌（PCA）是最常见的癌症，第二领先估计在美国死亡十多年。雄激素和雄激素受体（AR）调节前列腺的正常生长和功能。但是，雄激素和AR信号的异常调节途径与PCA发病机理和进展密切相关。因此，雄激素剥夺疗法（ADT）或靶向AR功能一直是针对高级前列腺的治疗策略的主要手段癌症。但是，当前的治疗策略无法治愈大多数PCA患者，因为耐药性和复发，最终发展转移性，cast割前列腺癌（MCRPC），这是一个致命的阶段疾病。对阿比特龙和恩扎拉胺的抗药性被认为是治疗失败和PCA复发。因此，阐明基础机制至关重要 PCA发病机理和耐药性，这可能有助于开发有效的新治疗克服PCA当前治疗的局限性的方法。 RNA M6A修饰由M6A沉积由三个核心亚基METTL3，METTL14和WTAP组成的甲基转移酶复合酶，可能具有作为基因表达的重要调节剂，可能影响mRNA转录，剪接，输出，稳定性和翻译。以前，我们报道了靶mRNA的mettl3催化的M6A修饰在包括PCA在内的人类癌症中扮演关键的致癌作用，但其在AR信号激活中的明确作用特别是在耐药的AR信号中仍然难以捉摸。我们的初步数据暗示M6A修改在增强子RNA（ERNAS）上，是从非编码增强子元素转录的调节性RNA，可能在PCA中还具有耐药性，这需要进一步的系统研究。该提议的目的是为了证明中心假设，即Mettl3介导的RNA M6A修饰在AR中起着至关重要的作用信号传导，PCA发病机理和耐药性。染色质相关调节剂的M6A甲基 RNA（Carrnas）和新生RNA将被映射，分析并与全基因组结合的结合 AR和转录机械。此外，核M6A读取器蛋白的YTHDC1的作用将在系统上是检查以调查其与AR和全基因组分布的反式激活的关系，因为它具有已知通过与M6A修饰的RNA结合来调节转录激活或抑制。损失 - 和功能收益实验将解决RNA M6A修饰在控制中的广泛影响 AR信号传导和下游基因表达的激活，因此将有助于发现分子 M6A修饰在PCA发病机理中作用的机制。最后，M6A修饰的影响使用异种移植物将探索使用耐药AR突变的AR信号调节操作 PCA小鼠模型以及患者衍生的异种移植（PDX）模型和测定面板将被放置在检查潜在的分子机制。我们提出的研究将成功揭示RNA M6A的作用修改AR信号传导和PCA发病机理，并有助于评估临床潜在药理 PCA中M6A修饰的抑制作用，尤其是转移性和耐药性PCA。