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

Author:

Zhang Haisheng1ORCID,Zhou Jiawang1ORCID,Li Jiexin1ORCID,Wang Zhaotong1ORCID,Chen Zhuojia2ORCID,Lv Ziyan1ORCID,Ge Lichen13ORCID,Xie Guoyou1ORCID,Deng Guoming1ORCID,Rui Yalan1ORCID,Huang Hongbing3ORCID,Chen Likun2ORCID,Wang Hongsheng1ORCID

Affiliation:

1. 1Guangdong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, P.R. China.

2. 2Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, P.R. China.

3. 3Department of Laboratory Medicine, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, P.R. China.

Abstract

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 VEGFA, a central regulator of neovasculature and blood vessel growth. m6A-sequencing and functional studies confirmed that m6A 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 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. Significance: 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.

Funder

The National Key Research and Development Program

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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