GPSM2 Promotes Pancreatic Cancer Progression Through METTL3-Mediated m6A Modification of YAP1 mRNA.

Pancreatic cancer poses a major therapeutic challenge due to its insidious onset and difficulty in early diagnosis. G-protein signalling modulator 2 (GPSM2), a member of the G-protein signalling regulator family, is highly expressed in various tumour tissues; however, its role in pancreatic cancer remains largely undefined. Yes-associated protein 1 (YAP1), a transcriptional co-activator, has been recognised as a central node in the growth-promoting signalling pathways of pancreatic cancer. Nevertheless, whether GPSM2 contributes to pancreatic cancer progression through the regulation of YAP1 has not yet been elucidated. In this study, transcriptome analysis of 183 pancreatic cancer patients from The Cancer Genome Atlas (TCGA) dataset identified GPSM2 as a survival-associated gene in pancreatic cancer. Functionally, we demonstrated that GPSM2 promotes colony formation and invasion of pancreatic cancer cells and was found to be mechanistically linked to the regulation of YAP1. Molecular investigations revealed that GPSM2 significantly upregulated YAP1 mRNA levels. Further analysis demonstrated that GPSM2 enhanced the N6-methyladenosine (m6A) modification of YAP1 mRNA in a METTL3-dependent manner. The KH3-4 domain of the m6A reader proteins IGF2BP2 and IGF2BP3 specifically recognised the m6A-modified YAP1 transcripts, thereby stabilising YAP1 mRNA and increasing YAP1 protein expression, which in turn promoted colony formation and invasion in pancreatic cancer cells. These findings provide novel insights into the molecular mechanisms underlying pancreatic cancer progression and may offer promising therapeutic targets for future intervention.