m6A modification of VEGFA mRNA by RBM15/YTHDF2/IGF2BP3 contributes to angiogenesis of hepatocellular carcinoma
Xiaoxin Xu
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorShuxiang Wu
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorYi Zhang
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorWeijie Fan
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorXinjian Lin
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorCorresponding Author
Kunqi Chen
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Correspondence Xu Lin and Kunqi Chen, Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, 1 Xue Fu North Rd, Fuzhou, Fujian 350122, China.
Email: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Xu Lin
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Department of Medical Microbiology, Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
Correspondence Xu Lin and Kunqi Chen, Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, 1 Xue Fu North Rd, Fuzhou, Fujian 350122, China.
Email: [email protected] and [email protected]
Search for more papers by this authorXiaoxin Xu
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorShuxiang Wu
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorYi Zhang
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorWeijie Fan
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorXinjian Lin
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Search for more papers by this authorCorresponding Author
Kunqi Chen
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Correspondence Xu Lin and Kunqi Chen, Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, 1 Xue Fu North Rd, Fuzhou, Fujian 350122, China.
Email: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Xu Lin
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, Fuzhou, China
Department of Medical Microbiology, Fujian Key Laboratory of Tumor Microbiology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, China
Correspondence Xu Lin and Kunqi Chen, Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, School of Basic Medical Sciences, 1 Xue Fu North Rd, Fuzhou, Fujian 350122, China.
Email: [email protected] and [email protected]
Search for more papers by this authorXiaoxin Xu and Shuxiang Wu contributed equally to this work.
Abstract
Vascular endothelial growth factor A (VEGFA) plays a critical role as a potent angiogenesis factor and is highly expressed in hepatocellular carcinoma (HCC). Although the expression of VEGFA has been strongly linked to the aggressive nature of HCC, the specific posttranscriptional modifications that might contribute to VEGFA expression and HCC angiogenesis are not yet well understood. In this study, we aimed to investigate the epitranscriptome regulation of VEGFA in HCC. A comprehensive analysis integrating MeRIP-seq, RNA-seq, and crosslinking-immunprecipitation-seq data revealed that VEGFA was hypermethylated in HCC and identified the potential m6A regulators of VEGFA including a m6A methyltransferase complex component RBM15 and the two readers, YTHDF2 and IGF2BP3. Through rigorous cell and molecular biology experiments, RBM15 was validated as a key component of methyltransferase complex responsible for m6A methylation of VEGFA, which was subsequently recognized and stabilized by IGF2BP3 and YTHDF2, leading to enhanced VEGFA expression and VEGFA-related functions such as human umbilical vascular endothelial cells (HUVEC) migration and tube formation. In the HCC xenograft model, knockdown of RBM15, IGF2BP3, or YTHDF2 resulted in reduced expression of VEGFA, accompanied by significant inhibition of tumor growth closely associated with VEGFA expression and angiogenesis. Furthermore, our analysis of HCC clinical samples identified positive correlations between the expression levels of VEGFA and the regulators RBM15, IGF2BP3, and YTHDF2. Collectively, these findings offer novel insights into the posttranscriptional modulation of VEGFA and provide potential avenues for alternative approaches to antiangiogenesis therapy targeting VEGFA.
CONFLICT OF INTEREST STATEMENT
The authors declare no conflicts of interest.
Open Research
DATA AVAILABILITY STATEMENT
The data that supports the findings of this study are available in the supplementary material of this article. The present study incorporates all data produced or analyzed throughout the research and is comprehensively presented in the published article and its supplementary information documents. Additional queries may be directed towards the corresponding author.
Supporting Information
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