Alternative Splicing Triggers Metabolic Transformation in Glioblastoma

Glioblastoma multiforme is a highly glycolytic tumor frequently characterized by expression of a constitutively activated EGF receptor (EGFR) mutant, EGFRvIII. Recent studies have shown that alternative splicing can induce metabolic reprogramming in cancer cells, but whether alternative splicing contributes to altered tumor metabolism in glioblastoma is unclear. Babic and colleagues found that EGFRvIII expression stimulated genome-wide alternative splicing changes and upregulation of MYC target genes including several glycolytic enzymes, consistent with the enhanced glycolytic phenotype of EGFRvIII-expressing xenograft tumors. This increase in alternative splicing was mediated by upregulation of the splicing factor heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) in EGFRvIII-mutant tumors downstream of mTOR activation. Elevated hnRNPA1 expression was correlated with EGFRvIII and glycolytic gene expression in primary glioblastoma samples and was associated with decreased overall survival. Furthermore, depletion of EGFRvIII diminished hnRNPA1 expression, impaired glucose uptake and the induction of glycolytic genes, and reduced glioma cell proliferation, suggesting that hnRNPA1-dependent splicing is required for the glycolytic phenotype in aggressive glioblastoma. In support of this idea, hnRNPA1 promoted alternative splicing of the MYC binding partner MYC-associated factor X (MAX) in EGFRvIII-expressing glioblastoma tumors; inclusion of exon 5 generated the Delta MAX splice variant, a truncated protein that has been implicated in MYC-driven transformation. Expression of Delta MAX, but not full-length MAX, stimulated glioblastoma cell proliferation and cooperated with MYC to enhance the expression of glycolytic genes. Moreover, Delta MAX expression was sufficient to rescue the induction of these genes in EGFRvIII-depleted cells, whereas knockdown of this splice variant inhibited glycolytic gene expression, reduced aerobic glycolysis, and impaired the growth of EGFRvIII-expressing xenografts. These findings identify generation of Delta MAX as an important mediator of MYC-dependent metabolic reprogramming in glioblastoma progression.

Babic I, Anderson ES, Tanaka K, Guo D, Masui K, Li B, et al. EGFR mutation-induced alternative splicing of Max contributes to growth of glycolytic tumors in brain cancer. Cell Metab 2013;17:1000–8.

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