Protein Arginine Methylation in Breast Cancer

乳腺癌中的蛋白质精氨酸甲基化

• 批准号: 10544497
• 负责人: Wei Xu
• 金额: $ 34.71万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10544497
• 关键词: Ablation; Address; Affect; Antibodies; Arginine; Attenuated; Automobile Driving; Binding; Binding Sites; Breast Cancer Cell; Breast Cancer Treatment; Breast Cancer cell line; Breast cancer metastasis; Bromodomain; Bromodomains and extra-terminal domain inhibitor; Cancer Etiology; Candidate Disease Gene; Cell Line; Cells; Cessation of life; ChIP-seq; Chromatin; Chromatin Remodeling Factor; Chromatin Structure; Clinical; Complex; Data; EP300 gene; Enhancers; Enzymes; Epigenetic Process; Estrogen Receptor alpha; Family; Foundations; Gene Chips; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Genomic approach; Genomics; Histones; Invaded; Knock-out; Link; MCF7 cell; MDA MB 231; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Mediator; Methylation; Methyltransferase; Mutation; Neoplasm Metastasis; Nuclear; Oncogene Activation; Oncogenes; Oncogenic; Paper; Pathway interactions; Permeability; Play; Post-Translational Protein Processing; Pre-Clinical Model; Prognostic Marker; Property; Proteins; Reaction; Recurrent Malignant Neoplasm; Regulatory Element; Resistance; Role; SMARCC1 gene; Signal Pathway; Site; Solid; Testing; Therapeutic Effect; Tumor Promotion; Verteporfin; Woman; Xenograft procedure; arginine methyltransferase; c-myc Genes; cancer cell; cancer recurrence; cancer subtypes; cancer therapy; cancer type; cell growth; cell motility; clinical investigation; coactivator-associated arginine methyltransferase 1; density; design; epigenetic drug; epigenetic therapy; in vivo; inhibitor; insight; knock-down; malignant breast neoplasm; migration; novel; novel therapeutics; overexpression; patient derived xenograft model; prevent; recruit; synergism; transcription factor; triple-negative invasive breast carcinoma; tumor; tumor growth; tumor progression

PROJECT SUMMARY/ABSTRACT Approximately 30% of all driver genes identified in cancer are related to chromatin structure and function. Distinct from common mechanisms involving altered expression or mutations of epigenetic modifiers, we identified post-translational modification of a chromatin regulator dependent mechanism for cancer progression and metastasis. BAF155, a component of SWI/SNF chromatin remodeling complex, is methylated by arginine methyltransferase CARM1 at a single site, R1064. Using methyl-BAF155 (me- BAF155) specific antibody for ChIP-seq, we found that me-BAF155 binding peaks are enriched with high- density H3K27Ac and H3K4me1 that feature the super-enhancers (SEs). SEs are important regulatory elements controlling oncogene expression in cancer cells. Because SEs recruit bromodomain containing protein BRD4, the expression levels of oncogenes are often sensitive to the BRD4 inhibitor JQ1. We showed that both JQ1 and CARM1 inhibitor treatment blocked the expression of me-BAF155 target genes and the recruitment of me-BAF155 and BRD4 to candidate genes in breast cancer cells. This leads to the hypothesis that me-BAF155 regulates oncogenes addicted to SEs thus promoting cancer metastasis. Aim 1 will examine the global me-BAF155 chromatin association upon treatment with JQ1 and CARM1 inhibitors. Because JQ1 is under clinical investigation for treatment of various cancer types, the novel mechanism of gene regulation via SEs in me-BAF155 driven cancer would suggest new therapeutic means to treat breast cancers with high levels of me-BAF155. We will test our hypothesis using different cell lines and patient- derived xenograft models. Furthermore, integration of microarray and me-BAF155 ChIP-seq data identifies key genes in the Hippo pathway dependent on BAF155 methylation. Therefore, our second hypothesis being tested (Aim 2) is that YAP activity potentiated by me-BAF155 contributes to cell growth, invasion and metastasis. Collectively, our study will validate the functional significance of me-BAF155 in driving cancer metastasis in different pre-clinical models and provide mechanistic insights into the oncogenic functions of me-BAF155. Epigenetic therapy has not been widely used for breast cancer treatment due to the lack of defined target and specific inhibitors for epigenetic enzymes. Our studies will lay solid foundation for the application of epigenetic drugs (e.g. CARM1 inhibitor) that target BAF155 methylation reaction in preventing and treating breast cancer metastasis.

项目摘要/摘要 在癌症中鉴定出的所有驱动基因中，约有30％与染色质结构和功能有关。 与涉及涉及表达改变或表观遗传修饰剂突变的常见机制不同，我们 鉴定出染色质调节剂依赖癌症机制的翻译后修饰 进展和转移。 BAF155是SWI/SNF染色质重塑复合物的组成部分，是 通过精氨酸甲基转移酶CARM1在单个位点R1064中甲基化。使用甲基-BAF155（me- BAF155）CHIP-SEQ的特异性抗体，我们发现ME-BAF155结合峰富含高 - 密度H3K27AC和H3K4ME1具有超级增强剂（SES）。 SES是重要的调节 控制癌细胞中癌基因表达的元素。因为SES募集含有的溴结构域 蛋白BRD4，癌基因的表达水平通常对BRD4抑制剂JQ1敏感。我们 表明JQ1和CARM1抑制剂治疗都阻止了ME-BAF155靶基因的表达 以及将ME-BAF155和BRD4募集到乳腺癌细胞中的候选基因。这导致了 假设ME-BAF155调节沉迷于SES的癌基因，从而促进癌症转移。目标1 将在用JQ1和CARM1抑制剂治疗后检查全球ME-BAF155染色质关联。 由于JQ1正在接受各种癌症类型的临床研究，因此 通过ME-BAF155驱动癌症中的SES调节基因调节将提出治疗乳房的新治疗方法 ME-BAF155的癌症。我们将使用不同的细胞系和患者 - 派生的异种移植模型。此外，微阵列和ME-BAF155 CHIP-SEQ数据的集成确定 河马途径中的关键基因取决于BAF155甲基化。因此，我们的第二个假设 接受测试（AIM 2）是ME-BAF155增强的YAP活性有助于细胞生长，侵袭和 转移。总的来说，我们的研究将验证ME-BAF155在驱动癌症中的功能意义 在不同的临床前模型中的转移，并提供机械见解 me-baf155。由于缺乏 定义的表观遗传酶的靶标和特异性抑制剂。我们的研究将为 靶向BAF155甲基化反应的表观遗传药物（例如CARM1抑制剂）在防止 并治疗乳腺癌转移。