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Glioma is the most prevalent and highly malignant form of adult brain cancer and is exceedingly difficult to manage. Neural stem cells and glial-determining factors have recently been implicated in glioma formation. Key transcriptional regulators of developmental glial genesis are expressed in glioma and have functional roles during glioma tumorigenesis. Nuak2, has been shown to be upregulated in many cancers and result in metastasis. However, the role of Nuak2 in glioma is not well defined. Using a combination of in vitro and in vivo studies, we found that loss of Nuak2 via CRISPR-mediated deletion results in decreased proliferation, migration, and tumorigenicity in glioma cell lines. Further, in a IUE mouse model of glioma CRISPR targeted deletion of Nuak2 resulting in increased survivability while over-expression of Nuak2 lead to faster tumor progression and death. Together, these studies demonstrate that Nuak2 has a vital role in glioma tumorigenicity and lays the groundwork for more in-depth mechanistic studies.

Glioblastoma multiforme, a form of malignant glioma, is a central nervous system (CNS) tumor associated with the worst prognosis in both adults and children. Effective treatments for this deadly cancer have continued to be elusive to this day. Several strategies have been employed to better understand malignant gliomas including genomics, cell survival, and cell fate determination. Previously we found that a glial cell determining factor, Nuclear Factor I-A (NFIA), is expressed in gliomas and has functional roles during glioma tumorigenesis. During CNS development, NFIA expression is regulated by distinct chromatin conformations that involve the transcription factors SOX9 and BRN2. The glial cell specific chromatin architecture is also present in glioma and modulation of the architecture has profound effects on tumor growth. Interestingly, the formation of this glial loop is not mediated by SOX9 and BRN2. A candidate factor for mediating formation of this chromatin architecture is the Mediator complex subunit 12 (MED12). Here we test whether MED12 is a component of the SOX9/BRN2complex, affects NFIA expression, and begin to determine what role MED12 plays in glioma tumorigenesis. Using dual gRNAs in a CRISPR/Cas9 system to delete MED12 expression from human glioma cell lines U87 and LN229, we found that MED12 is important for tumor growth, migration, and proliferation.