Methyltransferase like 3 enhances pinin mRNA stability through N6 -methyladenosine modification to augment tumourigenesis of colon adenocarcinoma

Abstract

New findings: What is the central question of this study? What is the role of pinin (PNN) in the malignant phenotype of colon adenocarcinoma cells and the underlying mechanism? What is the main finding and its importance? PNN mRNA can be stabilized and upregulated by methyltransferase like 3 (METTL3), which promotes glycolysis in colon adenocarcinoma and augments cell proliferation, migration and invasiveness. METTL3 and PNN might serve as potential targets for the treatment of colon adenocarcinoma.

Abstract: Colon adenocarcinoma (COAD) is a fatal malignancy with high morbidity and mortality rates globally. Pinin (PNN), a desmosome associated protein, has been revealed as a tumour driver in several malignancies. This study aims to probe the expression and role of PNN in COAD and the underlying mechanism. PNN was expressed at high levels in clinically collected COAD tumours and was linked to poor prognosis of patients. Downregulation of PNN reduced glucose uptake, lactate production and ATP levels in COAD cells and suppressed cell proliferation, migration and invasiveness. Methyltransferase like 3 (METTL3) was positively associated with PNN levels in COAD tumour tissues. RNA immunoprecipitation and N⁶ -methyladenosine (m⁶ A) quantification assays indicated that METTL3 enhanced PNN mRNA stability and expression in COAD through m⁶ A modification with the involvement of the m⁶ A 'reader' protein YT521-B homology domain family member 1. Downregulation of METTL3 reduced COAD cell glycolysis and proliferation in vitro and suppressed growth and metastasis of xenograft tumours in vivo, but further overexpression of PNN restored malignant behaviours of COAD cells and tumour growth. In summary, this study demonstrates that METTL3 promotes PNN mRNA stability and expression in COAD through m⁶ A modification, which augments glycolysis and proliferation of COAD cells and leads to the resultant tumour progression.

Keywords: METTL3; PNN; colon adenocarcinoma; glycolysis; m6A modification.