CASCADES, a novelSOX2super-enhancer associated long noncoding RNA, regulates cancer stem cell specification and differentiation in glioblastoma multiforme

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.

Crosstalk between SOX Genes and Long Non-Coding RNAs in Glioblastoma

“…The other regulatory mechanisms are also involved in SOX /lncRNA interplay in GBM ( Table 2 , Figure 3 ). LncRNA CASCADES is a SOX2 super-enhancer-associated lncRNA [ 85 ]. Super-enhancers represent clusters of enhancers in close genomic proximity that can work as independent regulatory regions or as a part of a large transcription regulatory network to enable the gradient expression of genes they regulated [ 95 , 96 ].…”

“…Super-enhancer-associated lncRNAs, lncRNAs transcribed from super-enhancers, have emerged as master regulators of cell fate determination and differentiation since they regulate the expression of genes essential for these processes by transcription factor trapping, chromatin modifications, recruitment of the RNA Pol II complex, and removal of the co-repressor function [ 98 , 99 ]. Shahzad et al discovered lncRNA CASCADES transcribed from a distal super-enhancer of SOX2 [ 85 ]. They revealed that CASCADES is an epigenetic regulator of SOX2 in GSCs and an essential factor for the maintenance of stemness in these cells [ 85 ].…”

“…Shahzad et al discovered lncRNA CASCADES transcribed from a distal super-enhancer of SOX2 [ 85 ]. They revealed that CASCADES is an epigenetic regulator of SOX2 in GSCs and an essential factor for the maintenance of stemness in these cells [ 85 ]. High CASCADES expression was detected in both primary and recurrent IDH-WT gliomas and correlated with poor overall survival [ 85 ].…”

“…They revealed that CASCADES is an epigenetic regulator of SOX2 in GSCs and an essential factor for the maintenance of stemness in these cells [ 85 ]. High CASCADES expression was detected in both primary and recurrent IDH-WT gliomas and correlated with poor overall survival [ 85 ]. The authors proposed a model in which CASCADES acts as a “transcription factor-trapper” to facilitate the expression of the SOX2 gene [ 85 ].…”

3D chromatin architecture and epigenetic regulation in cancer stem cells

“…Moreover, a recent study identified a lncRNA, Cancer stem cell associated distal enhancer of SOX2 ( CASCADES ) as a novel epigenetic regulator for glioma cancer stem cells (GCSCs) (Shahzad et al, 2020 ). Hi-C mapping revealed the CASCADES intronic enhancer interacted with SOX2 promoter in GCSCs.…”