The Role of Eya3 as a downstream target of EWS Fli1 in Ewings Sarcoma

Eya3 作为 EWS Fli1 下游靶标在尤文肉瘤中的作用

• 批准号: 8458187
• 负责人: Tyler P Robin
• 金额: $ 2.33万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8458187
• 关键词: 20 year old; 3' Untranslated Regions; Activator Appliances; Adult; Affect; Binding; Biological Assay; Biological Models; Bone Tissue; Cell Line; Cells; Characteristics; Child; Childhood; Chimeric Proteins; Chromosomal translocation; Clinical; Complex; DNA Binding Domain; DNA Repair; Data; Development; Disease; Disease Outcome; Disease Resistance; Drug Design; Drug Targeting; Ewings sarcoma; Family; Gene Targeting; Genetic Transcription; Homeodomain Proteins; Human; In Vitro; Laboratories; Luciferases; Malignant Bone Neoplasm; Malignant Childhood Neoplasm; Malignant Neoplasms; Mediating; Mediator of activation protein; MicroRNAs; Neoplasm Metastasis; Oncogene Proteins; Oncogenic; Outcome; Patients; Pediatric Neoplasm; Phenotype; Phosphoric Monoester Hydrolases; Play; Population; Program Development; Property; Protein Tyrosine Phosphatase; Proteins; Recurrence; Recurrent disease; Regulation; Relapse; Reporter; Resistance; Role; Stem cells; Transcriptional Activation Domain; Tyrosine; Work; chemotherapy; improved; in vivo; inhibitor/antagonist; malignant breast neoplasm; novel; outcome forecast; promoter; response; small molecule; soft tissue; therapeutic target; transcription factor; tumor; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): Ewing's sarcoma is an aggressive pediatric cancer of the bone and soft tissue. Patients that present with metastasis and patients who relapse have especially poor outcomes from this disease. Ewing's sarcoma is driven by a chromosomal translocation that produces the EWS/Fli1 fusion protein. We have identified the developmental protein, Eya3, as a downstream target of EWS/Fli1. Eya3 is important for DNA repair and is also found as part of a bipartite transcription factor complex with the Six family of homeobox proteins. The Eya/Six complex is important for development, but when inapropriately expresed after development is complete, promotes many oncogenic properties in other cancers, including proliferation, survival, and metastasis. However, the role of this complex in pediatric tumors, specificaly Ewing's sarcoma, has never before been examined. Similar to what is observed in other human tumors, inhibition of Eya3 in Ewing's sarcoma cells has a modest effect on proliferation and survival. However, we have discovered a novel role for Eya3 in Ewing's sarcoma, where Eya3 knockdown significantly increases Ewing's sarcoma cell chemosensitivity. This may be the result of the recently described ability of Eya3 to facilitate efficient DNA repair Additionally, since tumor-initiating cells (TIC) are implicated in treatment-resistant (chemoresistant) cancers, and since the binding partner of Eya3, Six1, increases TIC populations in breast cancer, we further examined whether Eya3 may modulate a TIC population in Ewing's sarcoma. Indeed, Eya3 knockdown decreases the tumor-initiating cell population. This data suggests that Eya3 may play an important role in mediating Ewing's sarcoma phenotypes associated with recurrent disease through multiple, and possibly inter- related, mechanisms. Studies outlined in this proposal aim to better understand the role of Eya3 in phenotypes associated with Ewing's sarcoma relapse, in an attempt to identify novel new drug targets that when inhibited, may reduce the poor clinical outcomes associated with Ewing's sarcoma. Studies performed will allow us to determine the mechanism of EWS/Fli1 regulation of Eya3 and then go on to further evaluate the role of Eya3 in modulating tumor-initiating cell populations and in chemoresistance. Eya3 has a unique tyrosine phophatase domain, as well as a transcriptional activation domain required to drive transcription along with its oncogenic partner, Six1. Work within this proposal will allow us to determine which activities of Eya3 are important for its roles in Ewing's sarcoma, so that we can better guide our targeting of Eya3 with small molecule inhibitors.

描述（由申请人提供）：尤因的肉瘤是骨骼和软组织的侵略性小儿癌。出现转移和复发的患者的患者因这种疾病的效果特别差。 Ewing的肉瘤是由产生EWS/FLI1融合蛋白的染色体易位驱动的。我们已经将发育蛋白EYA3确定为EWS/FLI1的下游靶标。 EYA3对于DNA修复很重要，也被发现是六个同型蛋白质家族的两部分转录因子复合物的一部分。 EYA/SIX络合物对于发育很重要，但是当发展后不恰当地阐明时，促进了其他癌症的许多致癌特性，包括增殖，生存和转移。但是，这种复合物在小儿肿瘤中的作用，特殊的尤因的肉瘤从未被检查过。与其他人类肿瘤中观察到的相似，在Ewing的肉瘤细胞中抑制EYA3对增殖和存活具有适度的作用。但是，我们在尤因的肉瘤中发现了EYA3的新作用，在Eya3敲低的情况下，Ewing的肉瘤细胞化学敏感性显着增加。 This may be the result of the recently described ability of Eya3 to facilitate efficient DNA repair Additionally, since tumor-initiating cells (TIC) are implicated in treatment-resistant (chemoresistant) cancers, and since the binding partner of Eya3, Six1, increases TIC populations in breast cancer, we further examined whether Eya3 may modulate a TIC population in Ewing's sarcoma.实际上，EYA3敲低减少了肿瘤的细胞群体。该数据表明，EYA3可能在介导Ewing的肉瘤表型中起着重要作用，这是通过多种，可能相关的机制与复发性疾病相关的。该提案中概述的研究旨在更好地了解EYA3在与Ewing肉瘤复发相关的表型中的作用，以识别新的新药物靶标，这些新药物可能会抑制后可能会减少与Ewing肉瘤相关的不良临床结果。进行的研究将使我们能够确定EWS/FLI1调节EYA3的机制，然后继续进一步评估EYA3在调节肿瘤发射细胞种群和化学耐药性中的作用。 EYA3具有独特的酪氨酸磷酸酶结构域，以及与其致癌伴侣一起驱动转录所需的转录激活结构域Six1。该提案中的工作将使我们能够确定EYA3的哪些活动对于其在Ewing的肉瘤中的作用很重要，因此我们可以更好地指导使用小分子抑制剂对EYA3的靶向。