N6-methyladenosine modification of RanGAP1 promotes colorectal cancer progression via CRABP2

Abstract

Ran GTPase activating protein 1 (RanGAP1) plays an important role in a variety of diseases; however, whether it affects colorectal cancer progression(COAD) is unclear. In this study, RanGAP1 was identified as a novel downstream gene of METTL3 in COAD by m6A epitranscriptomic microarray, MeRIP-seq and label-free proteomics analyses. RIP-qPCR and Luciferase reporter explored the molecular mechanism of m6A modifition. RNA-seq and label-free proteomics determined CRABP2 is a downstream target of RanGAP1. In vitro/vivo experiment verified the function upon RanGAP1 and CRABP2 silencing/overexpressing. The results showed RanGAP1 was highly expressed in COAD and CRABP2 was found to be positively correlated with RanGAP1. In addition, silencing RanGAP1/CRABP2 inhibited the tumorigenesis of COAD, while overexpressed RanGAP1 recused the influence of METTL3 sliencing in the malignant phenotype. Meanwhile, RanGAP1 affected the sensitivity of oxaliplatin and fluorouracil to COAD. Mechanistically, there is the direct interaction between METTL3/YTHDF1 and RanGAP1, and METTL3 mediates m6A methylation in the 3′UTR region of RanGAP1 mRNA and affects mRNA stability by recruiting YTHDF1. These results revealed RanGAP1 was a new downstream mechanism of METTL3-mediated m6A modification and promote COAD progression via CRABP2, which maybe is a potential therapeutic target for COAD.