CASCADES, a novel SOX2 super-enhancer associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma multiforme

Shahzad, U.; Li, C.; Johnston, M.; Wang, J. J.; Sabha, N.; Varn, F. S.; Riemenschneider, A.; Krumholtz, S.; Meda, P.; Smith, C.; Karamchandani, J.; Watts, J. K.; Verhaak, R. G. W.; Gallo, M.; Rutka, J. T.; Das, S.

doi:10.1101/2020.09.05.284349

bioRxiv · 10.1101/2020.09.05.284349

CASCADES, a novel SOX2 super-enhancer associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma multiforme

Shahzad, U.·Li, C.·Johnston, M.·Wang, J. J.·Sabha, N.·Varn, F. S.·Riemenschneider, A.·Krumholtz, S.·Meda, P.·Smith, C.·Karamchandani, J.·Watts, J. K.·Verhaak, R. G. W.·Gallo, M.·Rutka, J. T.·Das, S.

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Abstract

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, with a median survival of just over one year. The failure of available treatments to achieve remission in patients with GBM has been attributed to the presence of cancer stem cells (CSCs), which are thought to play a central role in tumor development and progression and serve as a treatment-resistant cell repository capable of driving tumor recurrence; in fact, the property of "stemness" itself may be responsible for treatment resistance. In this study, we identify a novel lncRNA, Cancer stem cell associated distal enhancer of SOX2 (CASCADES) that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in IDH-wild type GBM and significantly enriched in GSCs. Knockdown of CASCADES in GSCs results in differentiation towards a neuronal lineage in a cell- and cancer-specific manner. Bioinformatics analysis reveals that CASCADES functions as a super-enhancer associated lncRNA epigenetic regulator of SOX2. Our findings identify CASCADES as a critical regulator of stemness in GSCs and represent a novel epigenetic and therapeutic target for disrupting the cancer stem cell compartment in GBM.

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Shahzad, U., Li, C., Johnston, M., Wang, J. J., Sabha, N., Varn, F. S., Riemenschneider, A., Krumholtz, S., Meda, P., Smith, C., Karamchandani, J., Watts, J. K., Verhaak, R. G. W., Gallo, M., Rutka, J. T., Das, S.. 2020-09-06. CASCADES, a novel SOX2 super-enhancer associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma multiforme. https://doi.org/10.1101/2020.09.05.284349

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