Data from <i>N<sup>6</sup></i>-Methyladenosine Promotes Translation of VEGFA to Accelerate Angiogenesis in Lung Cancer

Abstract

<div>Abstract<p>Angiogenesis is hijacked by cancer to support tumor growth. RNA modifications such as <i>N6</i>-methyladenosine (m<sup>6</sup>A) can regulate several aspects of cancer, including angiogenesis. Here, we find that m6A triggers angiogenesis in lung cancer by upregulating VEGFA, a central regulator of neovasculature and blood vessel growth. m<sup>6</sup>A-sequencing and functional studies confirmed that m<sup>6</sup>A modification of the 5′UTR (untranslated region) of VEGFA positively regulates its translation. Specifically, methylation of a 5′UTR internal ribosome entry site (IRES) recruited the YTHDC2/eIF4GI complex to trigger cap-independent translation initiation. Intriguingly, the m<sup>6</sup>A methylation site A856 of the 5′UTR was located within the conserved upstream open reading frame (uORF) of VEGFA IRES-A, which overcomes uORF-mediated translation suppression while facilitating G-quadruplex–induced translation of VEGFA. Targeted specific demethylation of VEGFA m<sup>6</sup>A significantly decreased expression of VEGFA and reduced lung cancer cell–driven angiogenesis. <i>In vivo</i> and clinical data confirmed the positive effects of m<sup>6</sup>A modification of VEGFA on angiogenesis and tumor growth of lung cancer. This study not only reveals that the m<sup>6</sup>A/VEGFA axis is a potential target for lung cancer therapy but also expands our understanding of the impact of m<sup>6</sup>A modification of IRES in the 5′UTR of mRNA on translation regulation.</p>Significance:<p>Methylation of the 5′UTR IRES of VEGFA mRNA increases cap-independent translation via recruitment of the YTHDC2/eIF4GI complex, which stimulates angiogenesis to promote lung tumor growth.</p></div>