Role of UHRF1 in osteosarcoma and its relationship to RB

转移仍然是骨肉瘤治疗中最重要的致命并发症。中 发生转移的患者中，存活率不到五分之一。RB转录水平的遗传改变 辅阻遏物1（RB 1）基因与死亡率增加、转移和对化疗反应不良有关。 骨肉瘤的化疗然而，这种情况发生的确切机制仍然是 阐明。我们实验室的研究鉴定了UHRF 1（泛素样，含有PHD和RING Finger 结构域1），作为在骨肉瘤中上调的基因及其蛋白质过表达。UHRF 1是一种 一种参与表观遗传调控的多功能蛋白，已显示与RB相互作用。此夕h RB/E2 F通路直接调节UHRF 1的表达。我们的数据表明，针对UHRF 1 过表达显著增加了携带骨肉瘤肿瘤的小鼠的存活率， 转移的数量。本提案的目的是确定UHRF 1 有助于肿瘤进展，以帮助设计新的治疗干预措施， 骨肉瘤这些研究还评估了UHRF 1是否是大多数骨肉瘤的有效靶点， 携带RB 1突变的人为此，我们将明确UHRF 1在骨肉瘤发病机制中的作用， 发展，重点是其与RB 1的关系，并确定UHRF 1每个职能部门的作用 在骨肉瘤中与UHRF 1相关的迁移和侵袭中的结构域。这一提议验证了 由UHRF 1驱动的基因表达改变是肿瘤进展和低生存率的基础， 骨肉瘤这项工作的成功完成可能会直接影响UHRF的发展1 与骨肉瘤和其它具有UHRF 1的癌症的治疗干预相关的抑制剂 过度表达

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.