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Comprehensive analyses of HOXB13-regulated transcriptional programs critical for prostate cancer progression

Comprehensive analyses of HOXB13-regulated transcriptional programs critical for prostate cancer progression
HOXB13 调控的转录程序的综合分析对前列腺癌进展至关重要
批准号:
10364674
负责人:
Jindan Yu
金额:
$47.84万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-03-04 至 2023-02-28
关键词:
AcetylationAdultAmericanAndrogen ReceptorAndrogensBiological AssayCancer EtiologyCancer PatientCatalytic DomainCell CycleCell ProliferationCellsCessation of lifeChromatinClinicalClinical TrialsComplexDataDevelopmentDiagnosisDown-RegulationEnzymesEpigenetic ProcessEpithelialExcisionFASN geneFamilial prostate cancerFatty-acid synthaseFoundationsGene ExpressionGenesGenetic TranscriptionGerm-Line MutationGrowthHDAC3 geneHistone AcetylationHistone DeacetylaseHistonesHumanIn VitroLipidsLysineMalignant neoplasm of prostateMapsMass Spectrum AnalysisMediatingMediator of activation proteinMetastatic Prostate CancerMolecularMutationNeoplasm MetastasisNuclear ReceptorsOperative Surgical ProceduresPathway interactionsPatientsPharmaceutical PreparationsPlayProstateProstate-Specific AntigenProstatic NeoplasmsProteinsRadiation therapyRefractoryReportingRepressionResistance developmentRetinoidsRoleSignal TransductionSolid NeoplasmSpecimenTertiary Protein StructureTestingTherapeutic InterventionThyroid Hormone ReceptorTissue MicroarrayUp-RegulationVariantXenograft Modelandrogen deprivation therapyandrogen sensitivebasecancer initiationcastration resistant prostate cancercofactorearly onsetefficacy evaluationefficacy testingenzalutamidegene repressiongenetic corepressorgenomic locushomeodomainin vivoinhibitorlipid biosynthesislipid metabolismmenmutantnovelpatient derived xenograft modelprogramsprostate cancer cellprostate cancer cell lineprostate cancer modelprostate cancer progressionprostate carcinogenesisrecruitresistance mechanismstandard carestandard of caretargeted treatmenttranscription factortumortumor growth

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中文摘要
翻译
总结 前列腺癌(PCa)是美国男性中最常见的非皮肤癌。早期PCa 可以通过手术和/或放射治疗有效地消融。然而,转移性PCa仍然是一个 挑战,标准治疗是雄激素剥夺疗法(ADT)。然而,大多数PCa 患者在数月至数年的时间内对ADT产生耐药性,最终导致去势抵抗 PCa(CRPC)和广泛侵袭性肿瘤。这种耐药性的机制尚未完全了解, 但已经显示侵袭性PCa肿瘤积累脂滴以促进转移进展。 因此,克服ADT的关键是鉴定肿瘤转移的驱动基因,如脂肪生成基因, 这可能是治疗干预和长期治愈的有希望的靶点。在初步研究中,我们 发现HOXB 13,一种前列腺特异性的含有同源结构域的转录因子,在前列腺增生中下调。 与原发性PCa相比,我们发现HOXB 13在CRPC中的作用以前未被表征。 脂肪生成的转录抑制。我们发现了一种新的HOXB 13相互作用蛋白,组蛋白 脱乙酰酶3(HDAC 3),其关闭靶染色质以进行基因阻遏。值得注意的是,这种相互作用 被家族性PCa中报告的HOXB 13 G84 E突变破坏,并与早发性PCa相关 PCa。此外,我们的数据显示HDAC 3调节的基因与HOXB 13调节的基因明显重叠, 基因.与HOXB 13一样,HDAC 3抑制脂肪生成基因,如脂肪酸合成酶(FATIGUE),这是一种抑制脂肪生成的基因。 伴随着在靶基因处的关键组蛋白上的乙酰化的去除。因此,我们的中心假设是 HOXB 13通过表观遗传重塑招募HDAC 3来抑制脂肪生成基因表达, FASNi抑制剂将有效治疗具有低或G84 E突变型HOXB 13的CRPC。测试这些 目标1将研究HOXB 13相互作用和招募HDAC 3的分子机制。 蛋白质靶向染色质以催化组蛋白去乙酰化并抑制脂肪生成基因表达。我们将 我还研究了HOXB 13/HDAC 3介导的脂肪生成程序如何与AR交叉对话,AR在其中起着重要作用。 在诱导脂质代谢中的主要作用,并确定除FXR外的关键下游介质。目标2将 检测人类CRPC标本中HOXB 13及其关键靶基因的蛋白水平, HOXB 13及其G84 E突变体使用不同的PCa模型调节前列腺肿瘤发生,并评估其对前列腺癌的影响。 FASNi对使用HOXB 13-低或高异种移植物和PDX前列腺肿瘤生长和转移的功效 模型
英文摘要
Summary Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer in American men. Early-stage PCa can be effectively ablated with surgery and/or radiation treatments. However, metastatic PCa remains a challenge, and the standard treatment is androgen-deprivation therapy (ADT). However, a majority of PCa patients develop resistance to ADT over a period of months to years, ultimately resulting in castration-resistant PCa (CRPC) and widespread aggressive tumors. The mechanisms for this resistance are not fully understood, but it has been shown that aggressive PCa tumors accumulate lipid droplets for fueling metastatic progression. Thus, a key to overcoming ADT is to identify the driver genes of tumor metastasis, such as lipogenesis genes, which may be promising targets for therapeutic intervention and a long-term cure. In preliminary studies, we found that HOXB13, a prostate-specific homeodomain-containing transcription factor, is down-regulated in CRPC as compared to primary PCa, and we found a previously uncharacterized role of HOXB13 in transcriptional repression of lipogenesis. We identify a novel HOXB13-interacting protein, the histone deacetylase 3 (HDAC3), which closes target chromatin for gene repression. Of note, this interaction is disrupted by HOXB13 G84E mutation that has been reported in familial PCa and associated with early-onset PCa. Moreover, our data showed that HDAC3-regulated genes remarkably overlapped with HOXB13-regulated genes. Like HOXB13, HDAC3 inhibits lipogenic genes, such as fatty acid synthase (FASN), and this is accompanied by the removal of acetylation on key histones at target genes. Hence, our central hypothesis is that HOXB13 recruits HDAC3 to repress lipogenic gene expression through epigenetic remodeling and that FASN inhibitors (FASNi) will be effective in treating CRPC with low or G84E-mutant HOXB13. To test these hypotheses, Aim 1 will examine the molecular mechanisms by which HOXB13 interacts and recruits HDAC3 protein to target chromatin to catalyze histone de-acetylation and repress lipogenic gene expression. We will also investigate how this HOXB13/HDAC3-mediated lipogenic program cross talks with AR, which plays a major role in inducing lipid metabolism, and identify key downstream mediators in addition to FASN. Aim 2 will examine the protein levels of HOXB13 and its key target genes in human CRPC specimens, determine how HOXB13 and its G84E mutant regulate prostate tumorigenesis using diverse PCa models, and evaluate the efficacy of FASNi on prostate tumor growth and metastasis using HOXB13-low or -high xenograft and PDX models.
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FOXA1 regulates cytokine signaling and immune landscape in prostate cancer through ARID1A
  • 批准号:
    10681898
  • 项目类别:
  • 资助金额:
    $51.34万
  • 财政年份:
    2023
  • 负责人:
    Jindan Yu
  • 依托单位:
Comprehensive Analyses of HOXB13-regulated Transcriptional programs critical for Prostate Cancer Progression
  • 批准号:
    10904447
  • 项目类别:
  • 资助金额:
    $46.79万
  • 财政年份:
    2023
  • 负责人:
    Jindan Yu
  • 依托单位:
Society for Basic Urologic Research 2021 Annual Meeting: Molecular Mechanisms of Urological Diseases and Treatment Resistance
Role of NF90 in Prostate Cancer
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