<scp>NONO</scp> Maintains <scp>SREBP</scp> ‐Regulated Cholesterol Biosynthesis via <scp>RNA</scp> Binding in Neuroblastoma

High-risk neuroblastoma is associated with upregulation of cholesterol biosynthesis through increased expression of sterol regulatory element-binding protein (SREBP). NONO, a multifunctional nuclear RNA binding protein, is an established oncogene in neuroblastoma and can stabilize SREBP in breast cancer. Hence, here we addressed the unexplored question of NONO regulation of SREBP in neuroblastoma. We show NONO knockdown reduces cholesterol in neuroblastoma patient-derived tumor cell lines and high-risk neuroblastoma KELLY cells. NONO knockdown also reduces mRNA and protein expression of SREBP family members in KELLY cells. RNA-seq of NONO knockdown confirmed cholesterol synthesis pathway genes are downregulated. Further, only overexpression of NONO wild-type, rather than NONO mutant lacking the RNA recognition motif 1, could elevate SREBP levels after endogenous NONO knockdown, revealing the importance of NONO RNA binding activity. Finally, (R)-SKBG-1, a small molecule that modulates the RNA binding activity of NONO, hence altering its subnuclear distribution, significantly decreased cholesterol levels and SREBP target gene expression in KELLY cells. These results lend weight to manipulating NONO RNA binding as a potential therapeutic avenue for treating aggressive neuroblastoma.