RNA sequencing of U251 SERBP1 knockdown cells and RIP sequencing for the identification of SERBP1 targets in 293T cells

We have identified the RNA binding protein SERBP1 as a novel regulator of glioblastoma development. High SERBP1 expression is prevalent in glioblastomas and correlates with poor patient survival and response to chemo- and radio-therapy. SERBP1 is in fact upregulated in numerous tumor types and its high expression is a sign of poor prognosis in many cases. SERBP1 knockdown caused a major delay in tumor growth and impacted cancer relevant phenotypes in GBM and GSC lines; it decreased proliferation, viability, colony formation and invasion while promoting apoptosis. Genomic analyzes showed that SERBP1 binds GC rich motifs and regulates the expression of genes implicated in metabolic routes preferentially used by cancer cells (e.g. one carbon and methyl cycles). One important consequence is SERBP1 impact on epigenetic regulation. SERBP1 silencing decreased methionine production as well as H3K27me3 levels and led to up-regulation of several genes associated with neurogenesis, neuronal differentiation and neuronal function. Further analysis indicated that most of these genes are downregulated in GBM and epigenetic silencing might be the cause. By repressing these genes, SERBP1 likely contributes to GBM poorly differentiated state. In conclusion, SERBP1 is the first example of an RNA binding protein functioning as central regulator of cancer metabolism and indirect modulator of epigenetic regulation in GBM. Due its broad impact on cancer relevant processes and pathways, SERBP1 emerges as important oncogenic factor in GBM and other malignancies and as a potential therapeutic target.