Role of UHRF1 in osteosarcoma and its relationship to RB

UHRF1在骨肉瘤中的作用及其与RB的关系

基本信息

批准号：
10654716
负责人：
Claudia Andrea Benavente
金额：
$ 40.08万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10654716
关键词：
Biology Cell Cycle Regulation Cell Line Cells Childhood Solid Neoplasm Clinical Complication DNA Methylation Data Development Epigenetic Process Family Gene Expression Alteration Genes Genetic Transcription Goals Health Histone Acetylation Human In Vitro Incidence Invaded Knock-out Knockout Mice Laboratories Link Malignant Neoplasms Mediating Metastatic Neoplasm to the Lung Mus Mutation Neoplasm Metastasis PHD Finger Pathogenesis Pathway interactions Patients Phenotype Play Primary Bone Osteosarcoma Prognosis Promoter Regions Proteins Research Research Proposals Ring Finger Domain Role Site Structure of parenchyma of lung TP53 gene Testing Therapeutic Therapeutic Intervention Ubiquitin Ubiquitination Work anticancer treatment cancer therapy cell motility chemotherapy design effective therapy epigenetic regulation epigenome gain of function genetic corepressor histone methylation improved in vivo inhibitor inhibitor therapy knock-down loss of function migration mortality mouse model next generation novel novel therapeutic intervention osteosarcoma overexpression preservation recruit response therapeutic target tumor tumor progression tumorigenesis tumorigenic virtual

项目摘要

Metastasis remains the most significant fatal complication in the treatment of osteosarcoma. Among the patients who develop metastasis, less than 1 in 5 survive. Genetic alterations at the RB transcriptional corepressor 1 (RB1) gene have been associated with increased mortality, metastasis and poor response to chemotherapy in osteosarcoma. However, the precise mechanism through which this occurs remains to be elucidated. Studies in our laboratory identified UHRF1 (Ubiquitin-like, containing PHD and RING Finger domains 1), as a gene that is upregulated and its protein overexpressed in osteosarcoma. UHRF1 is a multifunctional protein involved in epigenetic regulation that has been shown to interact with RB. Further, the RB/E2F pathway directly regulates UHRF1 expression. Our data indicates that targeting UHRF1 overexpression dramatically increases survival in mice bearing osteosarcoma tumors and reduces the rate and number of metastases. The goal of this proposal is to determine the mechanism(s) through which UHRF1 contributes to tumor progression to help design novel therapeutic interventions for the treatment of osteosarcoma. These studies also evaluate whether UHRF1 is a valid target for most osteosarcomas or only those bearing RB1 mutations. For this, we will define the role of UHRF1 in osteosarcoma pathogenesis and progression, focusing on its relationship with RB1 and define the roles of each of the UHRF1 functional domains in the UHRF1-associated migration and invasion in osteosarcoma. This proposal tests the hypothesis that gene expression alterations driven by UHRF1 underlie tumor progression and poor survival in osteosarcoma. Successful completion of this work is likely to directly influence the development of UHRF1 inhibitors relevant for therapeutic intervention for osteosarcoma and other cancers with UHRF1 overexpression.

转移仍然是骨肉瘤治疗中最重要的致命并发症。在发生转移的患者，不到5分之一的生存。 RB转录的遗传改变 Corepressor 1（RB1）基因与死亡率增加，转移和对骨肉瘤的化学疗法。但是，发生这种情况的确切机制仍然是阐明。在我们的实验室中的研究确定了UHRF1（类似泛素样，含有PhD和环手指域1），作为一种上调的基因，其蛋白质在骨肉瘤中过表达。 UHRF1是一个参与表观遗传调节的多功能蛋白已显示与RB相互作用。此外， RB/E2F途径直接调节UHRF1表达。我们的数据表明针对UHRF1 过表达大大增加了骨肉瘤肿瘤的小鼠的存活，并降低了速率和速率转移数量。该提案的目的是确定UHRF1的机制有助于肿瘤发展有助于设计新型的治疗干预措施以治疗骨肉瘤。这些研究还评估了UHRF1是大多数骨肉瘤还是仅是那些带有RB1突变的人。为此，我们将定义UHRF1在骨肉瘤发病机理和进展，重点关注其与RB1的关系，并定义每个UHRF1功能的作用 UHRF1相关的迁移和骨肉瘤的侵袭中的域。该提案检验了假设 UHRF1驱动的基因表达改变是肿瘤进展的基础，而在骨肉瘤。成功完成这项工作可能会直接影响UHRF1的发展与UHRF1的骨肉瘤和其他癌症的治疗干预有关的抑制剂过表达。