Ying Yang 1, a master regulator of chronic inflammation in glioblastoma multiforme

Ying Yang 1，多形性胶质母细胞瘤慢性炎症的主要调节因子

• 批准号: 9515458
• 负责人: TOMASZ K KORDULA
• 金额: $ 19.38万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-15 至 2020-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9515458
• 关键词: Acute; Address; Affect; Anti-inflammatory; Astrocytes; Binding; Bioinformatics; Cell Line; Cell Nucleus; Cells; Chronic; Complex; Cytokine Activation; Cytokine Gene; Cytoplasm; Data; Development; Epigenetic Process; Family; Feedback; Gene Activation; Gene Expression; Gene Expression Regulation; Genes; Genetic Transcription; Glioblastoma; Growth; Human; Immunocompetent; In Vitro; Infection; Inflammation; Inflammatory; Injury; Knockout Mice; Lead; Lentivirus Vector; Link; Location; Malignant Neoplasms; Mediating; Modeling; Molecular; Monitor; Necrosis; Nuclear; Nude Mice; Oncogenic; Pathologic; Patients; Phenotype; Play; Publishing; Regulation; Regulatory Element; Role; Sampling; Survival Rate; TNFRSF5 gene; Testing; Therapeutic Intervention; Tissues; Transcriptional Activation; Yang; Yin-Yang; antitumor effect; chemokine; cytokine; experimental study; genome-wide; histone modification; human disease; in vivo; in vivo Model; inhibitor/antagonist; knock-down; member; novel; p65; prevent; programs; promoter; recruit; response; transcription factor; transcriptome sequencing; tumor; tumor growth; tumor microenvironment

Although inflammation is normally short-lived and quickly resolves to limit tissue injury, chronic inflammation is associated with several human cancer, including glioblastoma multiforme (GBM). GBMs are very aggressive tumors with very low patient survival rates. These tumors are characterized by necrosis and profound inflammation; with cytokines supporting GBM progression. The mechanisms by which chronic inflammation develops and persists in GBM regardless of multiple anti-inflammatory feedback loops remain elusive. One of the hallmarks of ongoing acute inflammation is cytokine-driven temporal activation of the p65/p50 NF-κB transcription factor, which drives expression of proinflammatory cytokines and chemokines. However, targeting activation of p65/p50 NF-κB has thus far not been beneficial. Nevertheless, p65/p50 NF-κB also initiates several feedback mechanisms, including induction of expression of RelB, a unique member of the NF-κB family which forms complexes with p50 and suppresses cytokine expression by mechanisms such as epigenetic silencing. This mechanism provide long- lasting effects that limit inflammation.We found that although expression of RelB is similarly induced in primary astrocytes and GBM, RelB suppresses cytokine expression in astrocytes, but unexpectedly enhances their expression in GBM cells. Thus, the anti-inflammatory RelB-driven feedback loop is converted into a feed-forward loop fueling chronic inflammation in GBM. We further found that this differential regulation depends on a transcription factor Yin Yang 1 (YY1), which is located in the cytoplasm of astrocytes but is exclusively present in the nuclei of GBM cells. We also found that YY1 interacts with RelB and the complexes of RelB/YY1/p50 may be responsible for the activation of cytokine expression in GBM cells. These preliminary data imply a critical role of YY1 in GBM and support a mechanistic model which explains the development and persistence of chronic inflammation associated with GBM. We propose that YY1 acts as a molecular switch in GBM converting RelB-dependent epigenetic silencing into RelB/YY1/p50- dependent transcriptional activation, which induces chronic inflammation and promotes GBM aggressiveness. We will: 1. establish a molecular mechanism of YY1-dependent gene activation and importance of YY1 in GBM in vitro, and 2. determine the role of YY1 in GBM development and progression in vivo.

尽管炎症通常是短暂的，并迅速解决以限制组织损伤，但慢性 炎症与几种人类癌症有关，包括多形胶质母细胞瘤（GBM）。 GBM是非常侵略性的肿瘤，患者的存活率非常低。这些肿瘤是 以坏死和深刻注射为特征；用支持GBM的细胞因子 进展。慢性炎症发展和持续在GBM中的机制 不管多种抗炎反馈回路是什么，仍然难以捉摸。的标志之一 正在进行的急性炎症是p65/p50 NF-κB的细胞因子驱动的临时激活 转录因子，驱动促炎细胞因子和趋化因子的表达。 然而，靶向p65/p50 NF-κB的激活迄今为止尚不有益。尽管如此， p65/p50 NF-κB还启动了几种反馈机制，包括诱导的表达 Relb是NF-κB家族的独特成员，该家族与P50形成复合物并抑制 通过表观遗传沉默等机制的细胞因子表达。这种机制可长期 限制注射的持久作用。我们发现，尽管RELB的表达相似 在原代星形胶质细胞和GBM中诱导的RERB抑制了星形胶质细胞中的细胞因子表达，但 出乎意料地增强了它们在GBM细胞中的表达。那，抗炎物驱动 反馈环将转换为馈送前向循环加油GBM中的慢性感染。我们 进一步发现，这种差异调节取决于转录因子yin yang 1（yy1）， 位于星形胶质细胞的细胞质中，但仅存在于GBM的核中 细胞。我们还发现YY1与RERB相互作用，RELB/YY1/P50的复合物可能是 负责GBM细胞中细胞因子表达的激活。这些初步数据意味着 YY1在GBM中的关键作用，并支持一种机械模型，该模型解释了发展和 与GBM相关的慢性炎症的持久性。我们建议yy1充当 GBM中的分子开关将RELB依赖性表观遗传沉默转化为RELB/YY1/P50- 依赖性转录激活，诱导慢性感染并促进GBM 侵略性。我们将：1。建立YY1依赖性基因激活的分子机制 YY1在体外GBM中的重要性和2。确定YY1在GBM发育中的作用 和体内进展。