STEM-08. RNA BINDING PROTEIN ZFP36L2 REGULATES GLIOMA STEM CELL MAINTENANCE

Post-transcriptional regulation of gene expression is well-controlled across normal tissues. Dysregulation of these regulatory events contributes to tumorigenesis and progression of cancer. RNA binding proteins (RBPs), as trans-acting factors, play a pivotal role in post-transcriptional RNA modification. We interrogated the TCGA glioblastoma microarray dataset, comparing glioblastoma to non-tumor with a differential expression level of at least twofold for RBP genes to identify candidate RBP genes that could contribute to glioblastoma malignancy. 36 RBP genes were significantly upregulated and 12 RBP genes were downregulated in glioblastoma. Among these RBP candidates, the Zinc Finger Protein 36, C3H1 Type-Like 2 or ZFP36L2, significantly correlated with poor survival. However, the biological function of ZFP36L2 is poorly understood. Here, we found that ZFP36L2 was highly expressed in the stem-like glioma cells, glioma stem cells (GSCs), compared to normal brain tissues. Targeting ZFP36L2 by short hairpin RNAs inhibited GSC proliferation, decreased self-renewal capacity in vitro, and inhibited tumor formation in vivo. Depletion of ZFP36L2 caused S-phase and G2/M-phase cell cycle arrest. Interrogating the upstream regulation of ZFP36L2 expression, we found CEBP/β overexpressed in GSC as a transcription factor binding to the ZFP36L2 promoter and regulated the ZFP36L2 expression. Downstream, HuR, another RNA binding protein encoded by the ELAVL1 gene, regulated ZFP36L2 at the mRNA level. Collectively, we are elucidating a novel RNA binding protein network essential for GSC maintenance, informing gene-regulatory mechanisms offering new opportunities for developing mechanistic based target therapeutics in neuro-oncology.