Mechanism and oncogenic role of lysine demethylase KDM5B in prostate cancer

赖氨酸脱甲基酶KDM5B在前列腺癌中的作用机制和致癌作用

基本信息

批准号：
9974582
负责人：
Zhenbang Chen
金额：
$ 28.27万
依托单位：
MEHARRY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-09-30 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974582
关键词：
Advanced Malignant Neoplasm Affect African American American Androgen Receptor Bypass CRISPR/Cas technology Cancer Patient Cell Aging Cell Nucleus Cells Chromosomes Data Development EZH2 gene Epigenetic Process FRAP1 gene Foundations Gene Chips Gene Expression Genetic Genetic Transcription Genetically Engineered Mouse Goals Growth HDAC4 gene Homologous Gene Human Immunocompetent Immunocompromised Host Incidence KDM1A gene KDM5B gene Knock-out Knockout Mice LNCaP Life Lysine Malignant Neoplasms Malignant neoplasm of prostate Modification Molecular Mus Mutant Strains Mice Mutate Mutation Names Nude Mice Oncogenic PC3 cell line PTEN gene Pathway interactions Penetrance Phosphoric Monoester Hydrolases Play Population Prostatic Neoplasms Proto-Oncogene Proteins c-akt Receptor Signaling Recurrent tumor Regulation Relapse Reporting Research Role SKP2 gene Sampling Secondary to Signal Pathway Signal Transduction Specimen TRAF6 gene Testing Transforming Growth Factor beta Treatment Efficacy Tumor Suppression Tumor Suppressor Genes Ubiquitination Xenograft procedure advanced prostate cancer androgen deprivation therapy anti-cancer cancer drug resistance cancer health disparity castration resistant prostate cancer caucasian American chromatin immunoprecipitation chromatin modification demethylation effective therapy health disparity histone demethylase histone modification in vivo insight male medical schools men mortality mouse model mutant novel novel therapeutic intervention novel therapeutics pre-clinical programs prostate cancer cell prostate cancer cell line prostate cancer progression prostate carcinogenesis protein transport receptor function senescence small molecule inhibitor tool tumor growth tumor progression tumorigenesis

项目摘要

Abstract Prostate cancer (PCa) is the leading life-threatening malignancy in American men and is disproportionally higher in African Americans (AAs) than other ethnic populations, underscoring a need to decode the underlying mechanism and to develop new and effective therapies to cure PCa. Despite androgen- deprivation therapy, relapse occurs in many PCa patients who eventually still die. The initiation and progression of PCa are driven by dysregulation of multiple oncogenic pathways secondary to genetic and epigenetic alterations of oncogenes and tumor suppressors. PTEN (phosphatase and tension homolog deleted on chromosome ten) is frequently deleted and/or mutated in various human cancers. Loss of PTEN leads to cancers with the aberration of AKT-mTOR, SKP2, TGF-β, and androgen receptor (AR) signaling pathways. KDM5B (lysine demethylase 5B, also named JARID1B), a JmjC domain- containing H3K4 histone demethylase, activates the gene expression of FOXA1, a crucial co-factor for AR function and signaling. Aberrant elevation of KDM5B is often found in human cancers including advanced PCa. FOXA1 mutation is 4-fold higher in AA PCa samples as compared to Caucasian American (CA) PCa samples, underscoring the importance of KDM5B/FOXA1 in PCa disparities. However, the mechanism and contributions of KDM5B to prostate tumorigenesis remain elusive. We recently demonstrated that KDM5B is noticeably increased in prostate tumors of Pten/Trp53 mutant mice, and that its levels are regulated by SKP2 and TRAF6 through ubiquitination. Our preliminary data reveal that KDM5B is higher in AA PCa samples than in CA PCa samples. In addition, PTEN loss results in an increase of KDM5B in mice, and KDM5B knockout (KO) decreased the levels of FOXA1 and AR in PCa cells. In aim 1 of this proposal, we will investigate the role of KDM5B in PTEN-null driven prostate tumorigenesis. With application of genetically-engineered mouse models, we will generate Pten/Kdm5b double mutants from Pten and Kdm5b mice, and define the effects of Kdm5b deficiency on the suppression of tumor progression in Pten-null mice. In aim 2, we will investigate the molecular mechanisms of KDM5B signaling network in prostate cancer. We will define KDM5B target gene by ChIP assay, KDM5B ubiquitination and mutation, its regulation by PTEN-AKT, SKP2 and TRAF6, and the relevance of KDM5B modification on EZH2, FOXA1, and AR signaling pathways using human PCa cell lines (PC3, LNCaP, C4-2B, and MDA PCa 2b). In aim 3, we will assess the effects of KDM5B inhibition on PCa growth of C4-2B and MDA PCa 2b cells, and its implications on PCa disparities. We will evaluate the impact of KDM5B KO and inhibition with compounds on the suppression of prostate tumor growth in xenografts and Luc/Pten mice. Results from this proposal should provide valuable insights into the mechanisms of epigenetic alterations in PCa, and a potential development of a novel therapeutic strategy to control PCa growth. This study should bring great benefit to all PCa patients and reduce/eliminate cancer disparities.

抽象的前列腺癌（PCA）是美国男性的潜在威胁生命的恶性肿瘤，并且不成比例非裔美国人（AAS）高于其他种族人口，强调了解码的需求基本机制并开发新的有效疗法来治疗PCA。尽管雄激素 - 剥夺疗法，继电器发生在许多有时仍然死亡的PCA患者中。主动性和 PCA的进展是由于继发于遗传和遗传和癌基因和肿瘤补充剂的表观遗传改变。 PTEN（磷酸酶和张力同源物在各种人类癌症中经常被删除和/或突变，在染色体上删除。损失PTEN 导致Akt-MTOR，SKP2，TGF-β和雄激素受体（AR）信号的畸变导致癌症途径。 KDM5B（赖氨酸脱甲基酶5b，也称为JARID1b），一个含有H3K4组蛋白的JMJC域脱甲基酶激活FOXA1的基因表达，FoxA1是AR功能和信号传导的关键辅助因素。 KDM5B的异常升高通常在包括晚期PCA在内的人类癌症中发现。 FOXA1突变是与白种人（CA）PCA样品相比，AA PCA样品中的4倍高4倍，强调了 KDM5B/FOXA1在PCA分布中的重要性。但是，KDM5B对前列腺肿瘤发生仍然难以捉摸。我们最近证明KDM5B明显增加了 PTEN/TRP53突变小鼠的前列腺肿瘤，其水平由SKP2和TRAF6通过泛素化。我们的初步数据表明，AA PCA样品中的KDM5B高于CA PCA 样品。此外，PTEN损失导致小鼠的KDM5B增加，而KDM5B敲除（KO）在本提案的目标1中，我们将调查 PTEN-NULL驱动前列腺肿瘤发生中的KDM5B。应用一般设计的鼠标模型，我们将生成PTEN和KDM5B小鼠的PTEN/KDM5B双突变体，并定义 KDM5B缺乏PTEN-NULL小鼠肿瘤进展的抑制。在AIM 2中，我们将调查前列腺癌中KDM5B信号网络的分子机制。我们将定义KDM5B目标基因通过CHIP分析，KDM5B泛素化和突变，其对PTEN-AKT，SKP2和TRAF6的调节，以及使用人PCA细胞系在EZH2，FOXA1和AR信号途径上修改KDM5B的相关性（PC3，LNCAP，C4-2B和MDA PCA 2B）。在AIM 3中，我们将评估KDM5B抑制对PCA的影响 C4-2B和MDA PCA 2B细胞的生长及其对PCA差异的影响。我们将评估影响 KDM5B KO和具有化合物抑制前列腺肿瘤生长的抑制作用和抑制作用 LUC/PTEN小鼠。该提案的结果应提供对机制机制的宝贵见解 PCA的表观遗传改变以及控制PCA的新型治疗策略的潜在发展生长。这项研究应为所有PCA患者带来巨大好处，并减少/消除癌症分布。