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

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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.