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

虽然炎症通常是短暂的，并能迅速消除以限制组织损伤，但慢性 炎症与几种人类癌症有关，包括多形性胶质母细胞瘤(GBM)。 基底节细胞瘤是一种侵袭性很强的肿瘤，患者存活率很低。这些肿瘤是 以坏死和严重炎症为特征；有支持基底膜的细胞因子 进步。慢性炎症在基底膜中发展和持续的机制 不管有多个消炎药，反馈回路仍然难以捉摸。标志之一就是 持续的急性炎症是细胞因子驱动的p65/p50 NF-κB的暂时激活 转录因子，驱动促炎细胞因子和趋化因子的表达。 然而，到目前为止，靶向激活p65/p50核因子-κB并没有什么好处。不过， P65/p50核因子-κB也启动了几种反馈机制，包括诱导 RepB是核因子-κB家族中独特的成员，它与p50形成复合体并抑制 通过表观遗传沉默等机制表达细胞因子。这一机制提供了长期的- 抑制炎症的持久作用。我们发现，尽管RelB的表达类似 在原代星形胶质细胞和GBM诱导下，RelB抑制星形胶质细胞中细胞因子的表达，但 出人意料地增强了它们在GBM细胞中的表达。因此，抗炎药物RelB驱动 反馈环被转化为前馈环，助长了GBM的慢性炎症。我们 进一步发现这种差异调控依赖于转录因子阴阳1(YY1)， 它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，RelB/YY1/p50的络合物可能是 负责激活GBM细胞中细胞因子的表达。这些初步数据表明， YY1在GBM中的关键作用，并支持一个解释发展和 与GBM相关的慢性炎症的持久性。我们建议YY1充当 GBM分子开关将RelB依赖的表观遗传沉默转化为RelB/YY1/p50- 依赖转录激活，诱导慢性炎症并促进GBM 咄咄逼人。我们将：1.建立依赖yy1基因激活的分子机制。 以及YY1在体外培养的GBM中的重要性，以及2.确定YY1在GBM发育中的作用。 以及在体内的进展。

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.