The pseudouridine synthase PUS7 is upregulated in glioblastoma and is required for GSC tumorigenesis.

  • Major Finding: The pseudouridine synthase PUS7 is upregulated in glioblastoma and is required for GSC tumorigenesis.

  • Mechanism: PUS7-mediated tRNA pseudouridylation is required for codon-specific translational control of GSC regulators.

  • Impact: Small-molecule inhibition of PUS7 may be a promising new therapeutic strategy in glioblastoma.

Pseudouridine is a nucleoside component of structural RNAs generated by the isomerization of uridine to pseudouridine and is the most common post-transcriptional RNA modification. This isomerization can be catalyzed by an RNA-dependent or RNA-independent mechanism, with the latter controlled by pseudouridine synthase (PUS) enzymes. To determine the role of PUS enzymes in glioblastoma multiforme (GBM), a highly aggressive type of brain cancer with a dismal prognosis, Cui, Yin, Zhang, and colleagues analyzed data from hundreds of GBM tumors and found PUS7 expression to be significantly upregulated in GBM compared with healthy controls and associated with a poorer prognosis. RNA interference or CRISPR-Cas9–mediated depletion of PUS7 in GBM stem cells (GSC) representing all major disease subtypes slowed growth and inhibited self-renewal capability. Moreover, immunodeficient mice transplanted with PUS7-depleted GSCs showed slowed tumor progression and longer survival compared with control mice. A drug screen identified small-molecule inhibitors of PUS7 that disrupted growth of GSCs and decreased pseudouridine levels at nanomolar concentrations, with no effect on control neural stem cells. Knockout of PUS7 rendered these compounds ineffective, suggesting specificity for PUS7. Mice engrafted with GSCs and subsequently treated with the inhibitor displayed reduction in tumor growth, reduced pseudouridine levels, and prolonged survival compared with vehicle-treated mice. RNA pseudouridine sequencing identified PUS7 targets in GSCs, revealing pseudouridylation of PUS7-regulated tRNA as a mechanism controlling codon-specific regulation of translation of GSC regulatory genes. These findings elucidate the mechanism of epitranscriptomic regulation of pseudouridine in GBM and the dependency of GSCs on PUS7-mediated tRNA pseudouridylation, and implicate PUS7 as a potential therapeutic target in GBM.

Cui Q, Yin K, Zhang X, Ye P, Chen X, Chao J, et al. Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis. Nat Cancer Aug 16 [Epub ahead of print].

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