Elucidating the role of the epigenetic regulator USP22 in human cancer

阐明表观遗传调节因子 USP22 在人类癌症中的作用

• 批准号: 8700344
• 负责人: Timothy James Stanek
• 金额: $ 4.27万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700344
• 关键词: Aftercare; Animal Model; Apoptosis; Biochemical; Biological Process; Cell Death; Cell Survival; Cells; Cessation of life; Complex; DNA Damage; DNA Repair; Data; Disease Progression; EZH2 gene; Enzymes; Epigenetic Process; Event; Genes; Genetic; Genetic Transcription; Genome; Genotoxic Stress; Growth; Histone Deacetylase; Histone H2A; Histone H2B; Human; Hydrolase; In Vitro; Knowledge; Lesion; Link; Malignant Neoplasms; Mediating; Methyltransferase; Modeling; Molecular Profiling; Neoplasm Metastasis; Oncogene Proteins; Oncogenes; Pathway interactions; Patients; Phenotype; Play; Polycomb; Process; Proteins; Reagent; Recruitment Activity; Refractory; Reporting; Resistance; Role; SAGA; Site; Stem cells; Stress; Ubiquitin; Xenograft Model; cancer cell; cancer stem cell; cell type; cofactor; genetic regulatory protein; histone acetyltransferase; in vivo; killings; member; neoplastic cell; novel; overexpression; p300/CBP-Associated Factor; preclinical study; programs; repaired; research study; small hairpin RNA; small molecule; therapeutic target; therapy resistant; transcription factor; tumor; tumor growth

DESCRIPTION (provided by applicant): Epigenetic regulators such as the polycomb proteins control critical biological functions in both normal stem cells and aggressive human cancer cell types. A gene signature that includes polycomb genes and additional genes co-regulated with polycomb genes was recently identified. The expression of this signature identifies tumors with the cancer stem cell phenotypes of aggressive growth, metastasis and therapy resistance. Most members of this 11- gene signature encode proteins with well-defined roles in human cancer. However the function of the signature member USP22 remained unknown. We recently reported that USP22 is a previously uncharacterized subunit of the human SAGA transcriptional cofactor complex. Within hSAGA, USP22 deubiquitylates histone H2A and H2B, thereby playing a central role in transcription. Furthermore, USP22 is recruited to specific genes by activators such as the MYC oncoprotein, where it is required for transcription. In support of a functional role within the polycomb/cancer stem cell signature, I have recently shown by genetic depletion that USP22 is required for protecting human cancer cells from death induced by genotoxic stress. In this proposal, I will define the precise biochemical events that USP22 overexpression triggers in aggressive human cancer cells in order to protect them from gentoxic stress and death. Ultimately, I will extend my findings from genetic depletion studies to assess whether pharmacological inhibition of USP22 can also be exploited to selectively induce apoptosis in transformed human cells.

描述（由申请人提供）：表观遗传调节剂例如多梳蛋白控制正常干细胞和侵袭性人类癌细胞类型中的关键生物功能。最近发现了一个基因特征，包括多梳基因和与多梳基因共同调控的其他基因。该特征的表达可识别具有侵袭性生长、转移和治疗抵抗的癌症干细胞表型的肿瘤。这 11 个基因特征的大多数成员编码的蛋白质在人类癌症中具有明确的作用。然而签名成员USP22的功能仍然未知。我们最近报道，USP22 是人类 SAGA 转录辅因子复合物的一个先前未表征的亚基。在 hSAGA 中，USP22 使组蛋白 H2A 和 H2B 去泛素化，从而在转录中发挥核心作用。此外，USP22 被 MYC 癌蛋白等激活剂招募到特定基因，这是转录所必需的。为了支持多梳/癌症干细胞特征中的功能作用，我最近通过基因耗竭表明，USP22 是保护人类癌细胞免遭基因毒性应激诱导死亡所必需的。在本提案中，我将定义 USP22 过表达在侵袭性人类癌细胞中触发的精确生化事件，以保护它们免受遗传毒性应激和死亡。最终，我将扩展基因缺失研究的发现，以评估 USP22 的药理学抑制是否也可用于选择性诱导转化的人类细胞凋亡。