N6-Methyladenosine Promotes Translation of VEGFA to Accelerate Angiogenesis in Lung Cancer

Abstract

Angiogenesis is hijacked by cancer to support tumor growth. RNA modifications such as N6-methyladenosine (m6A) can regulate several aspects of cancer, including angiogenesis. Here, we find that m6A triggers angiogenesis in lung cancer by upregulating vascular endothelial growth factor-A (VEGFA), a central regulator of neovasculature and blood vessel growth. m6A-sequencing and functional studies confirmed that m6A modification of the 5’UTR 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 m6A 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 m6A significantly decreased expression of VEGFA and reduced lung cancer cell-driven angiogenesis. In vivo and clinical data confirmed the positive effects of m6A modification of VEGFA on angiogenesis and tumor growth of lung cancer. This study not only reveals that the m6A/VEGFA axis is a potential target for lung cancer therapy but also expands our understanding of the impact of m6A modification of IRES in the 5’UTR of mRNA on translation regulation.

YTHDF2 Is a Therapeutic Target for HCC by Suppressing Immune Evasion and Angiogenesis Through ETV5/PD‐L1/VEGFA Axis

“…[ 11 ] The m 6 A site at IRES‐A suppresses uORF impairment while facilitating G‐quadruplex‐induced translation of VEGFA in lung cancers. [ 52 ] In the current study, we found that the mRNA expression of VEGFA was upregulated by YTHDF2 via ETV5 in HCC. These results indicate that the network by which YTHDF2 regulates the expression of VEGFA in different tumor cell backgrounds is complex.…”

Promotion of non-small cell lung cancer tumor growth by FHL2 via inducing angiogenesis and vascular permeability

“…VEGFA binds to VEGFR2 on the surface of endothelial cells to stimulate the AKT-mTOR downstream signaling pathway, thereby exerting its biological functions, such as angiogenesis and vascular permeability ( 20 , 32 , 33 ). VEGFA is upregulated in NSCLC tissues and has been associated with an increased risk of recurrence, metastasis, and death of patients with NSCLC ( 34 ). Hence, we further detected the VEGFA levels in the CM derived from NSCLC cells.…”

Maternal Supplementation with Ornithine Promotes Placental Angiogenesis and Improves Intestinal Development of Suckling Piglets

“…Mechanistically, Orn augmented VEGF-A expression by enhancing the mRNA stability of VEGF-A. N6-methyladenosine (m6A) modification, one of the most common modifications of mRNAs [ 43 ], was previously shown to boost the translation of VEGF-A to accelerate angiogenesis [ 44 ], suggesting m6A modification might be involved in the process of Orn in modulating VEGF-A mRNA stability, though this mechanism warrants further investigation. The above-described indicated that Orn promotes placental angiogenesis through regulating VEGF-A.…”