Functional Inhibition of Deubiquitylase HAUSP to Disrupt Glioblastoma Stem Cells

功能性抑制去泛素化酶 HAUSP 破坏胶质母细胞瘤干细胞

• 批准号: 9040115
• 负责人: Shideng Bao
• 金额: $ 36.26万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9040115
• 关键词: Affect; Brain Neoplasms; Cell Differentiation process; Cell Lineage; Cell Maintenance; Cells; Combined Modality Therapy; Data; Development; Embryo; Employee Strikes; Enzymes; Foundations; Glioblastoma; Glioma; Glomerular basement membrane antibody; Goals; Growth; Health; Herpesviridae; Heterogeneity; In Vitro; Maintenance; Malignant Neoplasms; Mediating; Molecular; Patients; Phenotype; Play; Population; Post-Translational Protein Processing; Post-Translational Regulation; Primary Brain Neoplasms; Proteins; Radiation; Recurrence; Resistance; Role; Solid; Stem cells; Therapeutic; Treatment Efficacy; Tumor Angiogenesis; Xenograft procedure; base; conventional therapy; improved; in vivo; inhibitor/antagonist; knock-down; nerve stem cell; novel; outcome forecast; overexpression; palliative; pre-clinical; preclinical study; self-renewal; small hairpin RNA; small molecule inhibitor; stem cell differentiation; stem cell therapy; temozolomide; therapeutic target; therapy resistant; transcription factor; tumor; tumor growth; tumorigenic; ubiquitin-protein ligase; ubiquitin-specific protease

 DESCRIPTION (provided by applicant): Glioblastomas (GBMs) are highly lethal brain tumors with extremely poor prognosis. The treatment of GBMs remains palliative due to therapeutic resistance. GBM displays striking cellular heterogeneity with a population of tumor-initiating cell (BTICs) or GBM stem cells (GSCs) at the apex of differentiation hierarchy. We previously demonstrated that GSCs promote therapeutic resistance, tumor angiogenesis and cancer invasion, indicating that therapeutic targeting of GSCs may effectively improve GBM treatment. The stem cell-like phenotype of GSCs is maintained by a set of core transcription factors including SOX2. The protein stability of SOX2 is tightly regulated by post-translational modifications. Our preliminary study indicated that SOX2 is regulated by both ubiquitylation (Ub) and deubiquitylation (Dub) in glioma cells. SOX2 is ubiquitylated by the E3 ubiquitin ligase, Huwe1, and then targeted for degradation in non-stem glioma cells. In GSCs, SOX2 protein is stabilized through deubiquitylation mediated by the deubiquitylase, HAUSP (Herpesvirus-Associated Ubiquitin-Specific Protease, also known as USP7). HAUSP is preferentially expressed in GSCs relative to neural progenitors. Targeting HAUSP by shRNA reduced SOX2 protein, promoted cell differentiation, disrupted GSC maintenance and potently inhibited GSC tumor growth. Functional inhibition of HAUSP by a small molecule inhibitor also inhibited tumor growth in orthotopic GBM xenografts and sensitized GSCs to radiation or temozolomide (TMZ). Based on these preliminary data, we hypothesize that HAUSP-mediated deubiquitylation antagonizes Huwe1-mediated ubiquitylation to stabilize SOX2 in the maintenance of GSCs, presenting a therapeutic target strategy to disrupts GSCs and suppress GBM tumor growth. We propose the following specific aims: 1. Determine the therapeutic impact of HAUSP inhibition on suppressing GBM tumor growth. 2. Define the molecular mechanisms underlying HAUSP-mediated GSC maintenance. 3. Evaluate synergy of HAUSP inhibition and current GBM therapies. The goal of this proposal is to evaluate the therapeutic potential of HAUSP inhibition in a preclinical study. We will determine whether targeting HAUSP can serve as an effective therapeutic strategy to improve GBM treatment. The proposed studies will lay a solid foundation for the development of novel anti-GSC therapeutics to effectively improve the survival of GBM patients.