Role of histone demethylase KDM5C in metastatic prostate cancer

组蛋白去甲基化酶 KDM5C 在转移性前列腺癌中的作用

• 批准号: 406024791
• 负责人: Professorin Dr. Jutta Kirfel
• 金额: --
• 依托单位: Institut für Pathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/406024791?language=en
• 关键词: Role; histone; demethylase; KDM5C; metastatic

Cancer metastasis is devastating and clinically challenging. For metastasis, cancer cells acquire increased migratory and invasive abilities, which are in principle subject to epigenetic control. In our previous study, we reported that the histone demethylase KDM5C (lysine demethylase 5C, also called JARID1C or SMCX) is over-expressed in prostate cancer and that KDM5C is a prognostic marker for prostate-specific antigen-relapse following radical prostatectomy. Here, we show that KDM5C is highly up-regulated in metastatic prostate cancer and that down-regulation of KDM5C leads to decreased migration and invasion of prostate cancer cells. In the proposed project, we aim to expand the knowledge about the underlying molecular mechanism and the impact of the histone demethylase KDM5C in metastatic prostate cancer. Firstly, we will examine whether KDM5C influences prostate cancer cells by performing RNA-Seq of KDM5C-depleted and/or KDM5C over-expressing cells in comparison to control cells. By this we will determine the signaling pathway(s) through which KDM5C may affect tumor cell progression. Secondly, we want to determine if KDM5C occupies target genes and demethylates H3K4me3/2 at their promoters by performing ChIP-Seq experiments. Stratification of gene expression and genome-wide pairwise comparison of KDM5C binding will identify direct KDM5C target genes. The results will provide epigenetic insights into how the down-regulation or inhibition of KDM5C may increase expression of metastasis-linked genes to enhance the invasive ability of prostate cancer cells. To gain new insight into KDM5C-mediated gene regulation we want to search for KDM5C-interacting proteins. Affinity purification and a mass spectrometric analysis of KDM5C-associated proteins will allow identifying unknown KDM5C-interacting proteins. The data emerging from this project will improve the knowledge about the molecular mechanisms taking place during development of metastatic prostate cancer and will answer the question whether targeting KDM5C is a strategy to reduce metastatic burden.

癌症转移是毁灭性的和临床上具有挑战性的。对于转移，癌细胞获得增加的迁移和侵袭能力，其原则上受到表观遗传控制。在我们之前的研究中，我们报道了组蛋白脱甲基酶KDM 5C（赖氨酸脱甲基酶5C，也称为JARID 1C或SMCX）在前列腺癌中过表达，并且KDM 5C是根治性前列腺切除术后前列腺特异性抗原复发的预后标志物。在这里，我们发现KDM 5C在转移性前列腺癌中高度上调，KDM 5C的下调导致前列腺癌细胞的迁移和侵袭减少。在拟议的项目中，我们的目标是扩大有关转移性前列腺癌中组蛋白去甲基化酶KDM 5C的潜在分子机制和影响的知识。 首先，我们将通过与对照细胞相比进行KDM 5C耗尽和/或KDM 5C过表达细胞的RNA-Seq来检查KDM 5C是否影响前列腺癌细胞。通过这一点，我们将确定KDM 5C可能影响肿瘤细胞进展的信号通路。其次，我们想通过进行ChIP-Seq实验来确定KDM 5C是否占据靶基因并在其启动子处使H3 K4 me 3/2去甲基化。基因表达的分层和KDM 5C结合的全基因组成对比较将鉴定直接的KDM 5C靶基因。这些结果将为KDM 5C的下调或抑制如何增加转移相关基因的表达以增强前列腺癌细胞的侵袭能力提供表观遗传学见解。为了获得对KDM 5C介导的基因调控的新见解，我们想要寻找KDM 5C相互作用蛋白。KDM 5C相关蛋白的亲和纯化和质谱分析将允许鉴定未知的KDM 5C相互作用蛋白。该项目的数据将提高对转移性前列腺癌发展过程中发生的分子机制的认识，并将回答靶向KDM 5C是否是减少转移负荷的策略的问题。