Targeting PUS7 suppresses tRNA pseudouridylation and glioblastoma tumorigenesis

Abstract

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.

Multi-omics approaches for biomarker discovery in early ovarian cancer diagnosis

“…reported that the expression and catalytic activity of PUS7 are critical for tumorigenesis. 73 Taken together, the above results indicate the potential importance of RNA modification activity for cancer screening and diagnosis.…”

PAMP-triggered genetic reprogramming involves widespread alternative transcription initiation and an immediate transcription factor wave

“…Stand-alone pseudouridine synthase-catalyzed introduction of pseudouridines is well established in tRNAs and spliceosomal snRNAs ( Spenkuch et al, 2014 ), but has also recently been found in mRNAs ( Borchardt et al, 2020 ) in several eukaryotic organisms, including plants ( Sun et al, 2019 ). Since pseudouridylation of tRNA can be important for translation of specific mRNAs encoding regulatory factors ( Cui et al, 2021 ) and snRNA pseudouridylation is linked to growth habit and stress adaptation in yeast, presumably via effects on alternative splicing ( Morais et al, 2021 ), the use of alternative PUS5 isoforms with distinct subcellular localization could have important ramifications for PTI-associated genetic reprogramming.…”

Rare and misincorporated DNA N6-methyladenine is a hallmark of cytotoxic stresses for selectively stimulating the stemness and proliferation of glioblastoma cells

“…Since it is the most common type of primary brain tumors and accounts for 81% of primary malignant intracranial tumors in human 35 , glioma is of intensive interest. Among three types of human gliomas, low-graded astrocytoma (A), anaplastic astrocytoma (AA), and glioblastoma (GBM) 28 , 35 , GBM is the most lethal one 36 – 38 . The median survival of patients with GBM remains < 16 months after diagnosis 39 .…”