Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis

Pseudouridine is the most frequent epitranscriptomic modification. However, its cellular functions remain largely unknown. Here we show that the pseudouridine synthase PUS7 is highly expressed in glioblastoma versus normal brain tissues, and high PUS7 expression levels are associated with worse survival in glioblastoma patients. The PUS7 expression and catalytic activity are required for glioblastoma stem cell (GSC) tumorigenesis. Mechanistically, we identified PUS7 targets in GSCs through small RNA pseudouridine sequencing, and showed that pseudouridylation of PUS7-regulated tRNA is critical for codon-specific translational control of key regulators of GSCs. Moreover, we identified chemical inhibitors for PUS7, and showed that these compounds prevented PUS7-mediated pseudouridine modification, suppressed tumorigenesis, and extended lifespan of tumor-bearing mice. Overall, we identified an epitranscriptomic regulatory mechanism in glioblastoma and provided preclinical evidence of a potential therapeutic strategy for glioblastoma.