N6-methyladenosine mRNA methylation of PIK3CB regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression
Menée en Chine à partir de données cliniques et génétiques portant sur 518 puis 522 patients atteints d'un adénocarcinome canalaire du pancréas puis menée in vitro et à l'aide de modèles murins, cette étude met en évidence un mécanisme par lequel la méthylation de la N6-méthyladénosine de l'ARN messager de PIK3CB favorise la progression des tumeurs présentant une déficience de la phosphatase PTEN en activant la voie de signalisation de la kinase AKT
Objective : Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers worldwide. Thus far, most drugs have failed to significantly improve patient survival. N6-methyladenosine (m6A) plays an important role in the progression of PDAC, but its aberrant regulation driven by germline variants in human diseases remains unclear. Design : We first performed an exome-wide association analysis in 518 PDAC patients with overall survival and replicated in an independent population containing 552 PDAC patients. Then, a series of biochemical experiments in vitro and in vivo were conducted to investigate potential mechanisms of the candidate variant and its target gene PIK3CB underlying the PDAC progression. Moreover, the PIK3CB-selective inhibitor KIN-193 was used to block PDAC tumour growth. Results We identified a missense variant rs142933486 in PIK3CB that is significantly associated with the overall survival of PDAC by reducing the PIK3CB m6A level, which facilitated its mRNA and protein expression levels mediated by the m6A ‘writer’ complex (METTL13/METTL14/WTAP) and the m6A ‘reader’ YTHDF2. The upregulation of PIK3CB is widely found in PDAC tumour tissues and significantly correlated with the poor prognosis of PDAC, especially in PTEN-deficient patients. We further demonstrated that PIK3CB overexpression substantially enhanced the proliferation and migration abilities of PTEN-deficient PDAC cells and activated AKT signalling pathway. Remarkably, KIN-193, a PIK3CB-selective inhibitor, is shown to serve as an effective anticancer agent for blocking PTEN-deficient PDAC. Conclusions These findings demonstrate aberrant m6A homoeostasis as an oncogenic mechanism in PDAC and highlight the potential of PIK3CB as a therapeutic target for this disease.