NONO regulates m5C modification and alternative splicing of mRNAs to drive gastric cancer progression

We identified non-POU domain-containing octamer-binding protein (NONO), a Drosophila behavior human splicing (DBHS) protein, was upregulated mRNA splicing factors in gastric cancer (GC). NONO was associated with poor prognosis in GC patients, and overexpression of NONO promoted GC cell proliferation, invasion and tumorigenesis in a GC xenograft model. Through RNA sequencing based transcriptomic profiling, we found that knockdown of NONO resulted in global changes in alternative splicing-intron retention, and identified PTEN mRNAs targeted by NONO. NONO directly bound to the intron of PTEN pre-mRNA and required interaction with NOP2/Sun RNA methyltransferase family member 2, NSUN2. Knockdown of NONO promotes PTEN overexpression in cells through abnormal m5C of PTEN mRNA. Taken together, our data revealed that NONO was a key regulator of mRNA m5C and splicing in GC, and that targeting NONO represents a novel and effective therapeutic strategy for the treatment of GC.