Protein Arginine Methylation in Chemotherapy Resistance

化疗耐药中的蛋白质精氨酸甲基化

基本信息

批准号：
9242960
负责人：
Wei Xu
金额：
$ 16万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9242960
关键词：
Address Adjuvant Aging Anthracyclines Antineoplastic Agents Arginine BRAF gene Biological Assay Biological Markers Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line Breast Cancer therapy Cancer Patient Categories Cell Culture Techniques Cell Line Cells ChIP-seq Clinical Clinical Management Colon Carcinoma Cytotoxic agent DNA Damage Databases Development Down-Regulation Drug Combinations Drug Controls Drug resistance Drug toxicity Fluorouracil Freezing Gene Targeting Genes Genetic Transcription Goals Histone H3 Human Implant In Vitro Individual Knock-in Knock-out Link Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of lung Mammary Neoplasms Maps Mass Spectrum Analysis Mediating Mediator of activation protein Methylation Methyltransferase Mitosis Modeling Multi-Drug Resistance Mutate Mutation Neoplasm Metastasis Oncologist Operative Surgical Procedures Pathologic Patients Pharmaceutical Preparations Prediction of Response to Therapy Proteins RNA Polymerase II Recurrence Reporting Research Resistance Resistance development Risk Signal Transduction Site Specimen Staining method Stains Testing The Cancer Genome Atlas Therapeutic Intervention Tissue Microarray Transforming Growth Factors United States Up-Regulation Woman Xenograft Model Xenograft procedure cancer diagnosis cancer therapy chemotherapy clinically relevant coactivator-associated arginine methyltransferase 1 cohort drug development drug sensitivity exome sequencing in vivo inhibitor/antagonist knock-down lung Carcinoma malignant breast neoplasm melanoma mortality mouse model mutant new therapeutic target novel oncoprotein p21 outcome forecast overexpression personalized approach polyclonal antibody predicting response prevent receptor resistance mechanism response taxane triple-negative invasive breast carcinoma tumor tumor progression tumor xenograft zinc finger nuclease

项目摘要

PROJECT SUMMARY Chemotherapy continues to be an important component of therapy for breast cancer, given to reduce the risk of metastatic recurrence. Although response (sensitivity) or lack of response (resistance) to chemotherapy is associated with prognosis, there is currently no validated commercial assay available which specifically predicts response to chemotherapy. Personalized approaches to cancer therapy are needed to select a drug or combination of drugs to which a tumor is most sensitive, and to avoid the toxicity of drugs to which the tumor is or becomes resistant. Such biomarker will assist oncologists in the daily clinical management of aging patients who are fragile to multiple chemotherapies and triple negative breast cancer patients whose major treatment option is chemotherapy. Coactivator associated arginine methyltransferase 1 (CARM1) is a protein arginine (R) methyltransferase which can methylate histone H3 and a variety of non-histone substrates. We recently identified a mediator of RNA polymerase II transcription subunit 12 (MED12) as a novel substrate for CARM1. The proposed project will determine whether methylation of MED12 is a predictor for chemo-sensitivity in breast cancer. We have mapped the methylation sites of MED12 to R1862 and R1912. Coincidently, mutations on R1862 had been reported in lung and cervical cancers, and mutations on R1912 had been found in a melanoma patient who developed resistance to BRAF inhibitor. We found that overexpression of MED12 wild-type, but not MED12R1862K,R1912K mutant, increased sensitivity of HEK293 cells to 5-FU and anthracyclines. Interestingly, the MED12 methylation dependent mechanism is distinct from activation of TGF-βR signaling as reported for complete knockout of MED12 in lung and colon cancers. Further, we have identified targets regulated by methylated MED12 that may determine chemo-sensitivity. We hypothesize that methylation of MED12 by CARM1 represents an important mechanism conferring chemosensitivity. The proposed research will directly address (1) whether MED12 methylation predicts sensitivity of breast cancer cells to commonly used chemotherapies in cell culture and xenograft tumor models; (2) define the mechanism of methylated-MED12 controlled chemosensitivity; and (3) test the clinical relevance of the MED12 methylation in chemo- resistance using large cohorts of clinical specimens. The goal is to delineate the methylation dependent mechanism for chemotherapy resistance and uncover new targets for therapeutic intervention.

项目摘要化学疗法仍然是乳腺癌治疗的重要组成部分，以减少转移性复发的风险。虽然反应（灵敏度）或缺乏反应（电阻）对化学疗法与预后有关，目前尚无验证的商业测定这特别预测了对化学疗法的反应。个性化的癌症治疗方法是需要选择肿瘤最敏感的药物或组合的药物，并避免毒性肿瘤所吸引或变得抗性药物的药物。这样的生物标志物将协助每日肿瘤学家对多种化学疗法和三重阴性乳房脆弱的老化患者的临床管理主要治疗选择的癌症患者是化学疗法。相关精氨酸甲基转移酶1（CARM1）是蛋白精氨酸（R）甲基转移酶可以甲基化组蛋白H3和多种非历史底盘底物。我们最近确定了一个调解人 RNA聚合酶II转录亚基12（MED12）作为CARM1的新底物。提议项目将确定Med12的甲基化是否是乳腺癌化学敏感性的预测因子。我们已将MED12的甲基化位点映射到R1862和R1912。巧合的是，R1862的突变据报道在肺和宫颈癌中，在黑色素瘤中发现了R1912的突变对BRAF抑制剂产生抗性的患者。我们发现Med12野生型的过表达，但是不是MED12R1862K，R1912K突变体，增加了HEK293细胞对5-FU和蒽环类细胞的敏感性。有趣的是，Med12甲基化依赖机制与TGF-βR信号的激活不同据报道，在肺癌和结肠癌中完全淘汰了Med12。此外，我们已经确定了目标由甲基化的Med12调节，可能决定化学敏感性。我们假设该甲基化 CARM1的MED12代表了一个重要的机制会议化学敏感性。提议研究将直接解决（1）MED12甲基化预测是否对乳腺癌细胞的敏感性对在细胞培养和Xenographic肿瘤模型中常用的化学疗法；（2）定义机制甲基化 - 媒体12的控制化学敏感性；（3）测试Med12甲基化的临床相关性在化学抗性中，使用大量临床标本。目的是描述甲基化化学疗法耐药性的依赖机制，并发现了治疗干预的新靶标。