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

• 批准号: 10204766
• 负责人: Zhenbang Chen
• 金额: $ 4.18万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 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/10204766
• 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

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.

摘要 前列腺癌（PCa）是美国男性中威胁生命的主要恶性肿瘤， 非洲裔美国人（AAs）高于其他种族人群，强调需要解码 潜在的机制，并开发新的和有效的治疗方法来治愈PCa。尽管有雄激素- 剥夺治疗，复发发生在许多PCa患者谁最终仍然死亡。启动和 前列腺癌的进展是由继发于遗传和 癌基因和肿瘤抑制基因的表观遗传改变。磷酸酶和张力同源物 在10号染色体上缺失）在各种人类癌症中经常缺失和/或突变。PTEN缺失 导致AKT-mTOR、SKP 2、TGF-β和雄激素受体（AR）信号传导异常的癌症 途径。KDM 5 B（赖氨酸脱甲基酶5 B，也称为JARID 1B），一种含有JmjC结构域的H3 K4组蛋白 脱甲基酶激活FOXA 1的基因表达，FOXA 1是AR功能和信号传导的关键辅因子。 KDM 5 B的异常升高经常在包括晚期PCa在内的人类癌症中发现。FOXA 1突变是 4-AA PCa样本中的PCa浓度比白种美国人（CA）PCa样本高1倍，强调了 KDM 5 B/FOXA 1在PCa差异中的重要性。然而，KDM 5 B的机制和贡献， 前列腺肿瘤发生仍然难以捉摸。我们最近证明，KDM 5 B在 Pten/Trp 53突变小鼠的前列腺肿瘤，其水平通过SKP 2和TRAF 6调节， 泛素化我们的初步数据表明，KDM 5 B在AA PCa样品中高于CA PCa样品 样品此外，PTEN缺失导致小鼠中KDM 5 B增加，KDM 5 B敲除（KO） 降低PCa细胞中FOXA 1和AR的水平。在本提案的目标1中，我们将研究 KDM 5 B在PTEN无效驱动的前列腺肿瘤发生中的作用应用基因工程小鼠 模型，我们将从Pten和Kdm 5 b小鼠中产生Pten/Kdm 5 b双突变体，并定义 Kdm 5 b缺陷对Pten缺失小鼠中肿瘤进展的抑制。在目标2中，我们将研究 KDM 5 B信号网络在前列腺癌中的分子机制。我们将确定KDM 5 B的靶基因 通过ChIP分析，KDM 5 B泛素化和突变，其受PTEN-AKT，SKP 2和TRAF 6的调节，以及KDM 5 B的蛋白质水平。 使用人PCa细胞系研究KDM 5 B修饰对EZH 2、FOXA 1和AR信号通路的相关性 (PC3、LNCaP、C4-2B和MDA PCa 2b）。在目的3中，我们将评估KDM 5 B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 KDM 5 B KO的抑制和化合物对异种移植物中前列腺肿瘤生长的抑制作用， Luc/Pten小鼠。该提案的结果应提供宝贵的见解， PCa的表观遗传学改变，以及控制PCa的新治疗策略的潜在发展 增长这项研究将为所有PCa患者带来巨大的益处，并减少/消除癌症差异。