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.

虽然炎症通常是短暂的并且很快就会消退以限制组织损伤，但慢性炎症 炎症与多种人类癌症有关，包括多形性胶质母细胞瘤（GBM）。 GBM 是一种侵袭性很强的肿瘤，患者存活率非常低。这些肿瘤是 以坏死和严重炎症为特征；含有支持 GBM 的细胞因子 进展。 GBM 中慢性炎症发生和持续的机制 尽管多重抗炎反馈回路仍然难以捉摸。的标志之一 持续的急性炎症是细胞因子驱动的 p65/p50 NF-κB 暂时激活 转录因子，驱动促炎细胞因子和趋化因子的表达。 然而，迄今为止，针对 p65/p50 NF-κB 的激活并没有带来好处。尽管如此， p65/p50 NF-κB 还启动多种反馈机制，包括诱导 RelB，NF-κB 家族的独特成员，与 p50 形成复合物并抑制 通过表观遗传沉默等机制表达细胞因子。该机制提供了长期 限制炎症的持久效果。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，RelB 抑制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。因此，RelB 驱动的抗炎 反馈回路被转换为前馈回路，加剧 GBM 的慢性炎症。我们 进一步发现这种差异调节依赖于一个转录因子阴阳1（YY1）， 位于星形胶质细胞的细胞质中，但仅存在于 GBM 的细胞核中 细胞。我们还发现YY1与RelB相互作用并且RelB/YY1/p50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解释其发展和的机制模型 与 GBM 相关的慢性炎症持续存在。我们建议 YY1 作为 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，诱导慢性炎症并促进 GBM 攻击性。我们将： 1.建立YY1依赖性基因激活的分子机制 以及YY1在体外GBM中的重要性，以及2.确定YY1在GBM发育中的作用 和体内进展。