<i>CASCADES</i>, a novel <i>SOX2</i> super‐enhancer‐associated long noncoding <scp>RNA</scp>, regulates cancer stem cell specification and differentiation in glioblastoma
Uswa Shahzad, Marina Nikolopoulos, Christopher Li, Michael J. Johnston, Jenny Jing Wang, N. Sabha, Frederick S. Varn, Alexandra N. Riemenschneider, Stacey Krumholtz, Pranathi M. Krishnamurthy, Christian A. Smith, Jason Karamchandani, Jonathan K. Watts, Roel G.W. Verhaak, Marco Gallo, James T. Rutka, Sunit Das
Abstract
Glioblastoma is the most common primary malignant brain tumor in adults, with a median survival of just over 1 year. The failure of available treatments to achieve remission in patients with glioblastoma (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 long noncoding RNA (lncRNA), cancer stem cell-associated distal enhancer of SOX2 (CASCADES), that functions as an epigenetic regulator in glioma CSCs (GSCs). CASCADES is expressed in isocitrate dehydrogenase (IDH)-wild-type GBM and is 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 that represents a novel epigenetic and therapeutic target for disrupting the CSC compartment in glioblastoma.