Cooperativity of TMPRSS2-ERG fusion with p53 inactivation in prostate cancer pathogenesis
TMPRSS2-ERG 融合与 p53 失活在前列腺癌发病机制中的协同作用
基本信息
- 批准号:10557878
- 负责人:
- 金额:$ 48.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-01 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAgeAge MonthsAmericanBindingCDK2 geneCancer EtiologyCancer PatientCancerousCell Cycle ProgressionCellsCessation of lifeChromatinCodeComplexDataDevelopmentElderlyEpigenetic ProcessExonsGene DeletionGene ExpressionGene FusionGene MutationGene ProteinsGene TargetingGenesGenetic TranscriptionKDM1A geneKnock-outLesionMalignant neoplasm of prostateMediatingMetastatic Prostate CancerMolecularMolecular Mechanisms of ActionMusMutationN-terminalOncogene ETSOncogenicPathogenesisPathway interactionsPatientsPhosphorylationPrecision therapeuticsProstateProstate Cancer therapyProstatic Intraepithelial NeoplasiasReaderRegulationRoleSignal PathwaySignal TransductionSpecimenTMPRSS2 geneTP53 Gene InactivationTP53 geneTestingThreonineTransgenesadvanced prostate cancerandrogen sensitiveanti-cancerclinically significantdemethylationdesigndisorder subtypeeffective therapygenomic locusmenmolecular subtypesnext generation sequencingnovelnovel therapeuticsoverexpressionprogramspromoterprostate cancer cellprostate carcinogenesistranscription factortranscriptome
项目摘要
PROJECT SUMMARY
Prostate cancer (PCa) is the second leading cause of cancer death in American men. The TMPRSS2-ETS
related gene (ERG) fusion (termed T2-ERG), juxtaposing the strong androgen-responsive TMPRSS2 gene
promoter with the coding region of the putative oncogene ERG, occurs in approximately 50% of all PCa in
patients. It has been inferred that overexpressed truncated T2-ERG is a key player in PCa pathogenesis. Notably,
a number of studies show that overexpression of T2-ERG protein alone is insufficient to trigger formation of PCa
in mice unless at very advanced age (> 24 months), implying the requirement of additional lesions in T2-ERG
overexpression-induced PCa pathogenesis. By analyzing the NGS data from > 1500 cases of PCa patient
specimens, we showed that T2-ERG fusion and p53 inactivation (loss of p53 tumor suppressor function due to
TP53 gene deletion and/or mutation) co-occurred in both primary and metastatic PCa, supporting the notion that
T2-ERG fusion and TP53 inactivation cooperate to drive PCa pathogenesis and progression. We demonstrated
that prostate-specific T2-ERG transgene and Trp53 knockout (T2-ERG+/p53-) not only largely enhanced ERG
target gene expression, but also induced high-grade prostatic intraepithelial neoplasia (HGPIN) and cancerous
lesions in mice at 12-15 months of age. Mechanistically, we identified LSD1 as a direct binding partner of ERG
protein and showed that cyclin-dependent kinase-2 (CDK2) phosphorylates LSD1 at threonine 59 (T59-p), which
disrupts LSD1 interaction with HP1γ, an epigenetic `reader' of H3K9me2/3 and induces demethylation of these
transcription repressive chromatin marks at ERG target gene loci. Based on these novel preliminary data, we
hypothesize that in p53-proficient cells the oncogenic potential of T2-ERG is constrained under a transcription
repressive chromatin state through association with the LSD1-HP1γ complex. However, p53 inactivation induces
loss or downregulated expression of p21WAF1, aberrant activation of CDKs and accelerated cell cycle progression,
which in turn triggers LSD1 T59-p-mediated disassociation of HP1γ from LSD1, HP1γ eviction from chromatin
due to accelerated cell cycle progression-associated H3S10 phosphorylation (H3S10-p), thereby promoting
H3K9me demethylation at ERG target gene loci, oncogenic reprogramming of ERG transcriptome, and PCa
pathogenesis and progression. To test this hypothesis, we will determine the molecular basis and regulation of
LSD1 phosphorylation-mediated inhibition of LSD1-HP1γ interaction in T2-ERG+/p53- PCa cells (Aim 1), define
the mechanism and extent to which LSD1 enzymatic activity and T59 phosphorylation regulates ERG
transcriptional program in T2-ERG+/p53- PCa cells (Aim 2), and determine the clinical significance of the interplay
between ERG and p53 signaling and anti-cancer efficacy of targeting LSD1 and ERG pathways in T2-ERG+/p53-
PCa (Aim 3). Findings from the proposed studies will shed new light on molecular mechanisms of PCa
pathogenesis and could lead to development of novel therapeutics for the treatment of T2-ERG+/p53- PCa.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Liewei Wang其他文献
Liewei Wang的其他文献
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TSPYL 基因对 CYP 转录的药物基因组调控
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