Abstract
RNA N6-methyladenosine is a key step of posttranscriptional modulation that is involved in governing gene expression. The m6A modification catalyzed by Mettl3 has been widely recognized as a critical epigenetic regulation process for tumorigenic properties in various cancer cell lines, including bladder cancer. However, the in vivo function of Mettl3 in bladder cancer remains largely unknown. In our study, we found that ablation of Mettl3 in bladder urothelial attenuates the oncogenesis and tumor angiogenesis of bladder cancer using transgenic mouse model. In addition, conditional knockout of Mettl3 in K14+ bladder cancer stem cell population leads to inhibition of bladder cancer progression. Coupled with the global transcriptome sequencing and methylated RNA immunoprecipitation sequencing results, we showed that deletion of Mettl3 leads to the suppression of tyrosine kinase endothelial (TEK) and vascular endothelial growth factor A (VEGF-A) through reduced abundance of m6A peaks on a specific region. In addition, the depletion of Mettl3 results in the decrease in both messenger RNA (mRNA) and protein levels of TEK and VEGF-A in vitro. Taken together, Mettl3-mediated m6A modification is required for the activation of TEK–VEGF-A-mediated tumor progression and angiogenesis. Our findings may provide theoretical basis for bladder cancer treatment targeting Mettl3.
Highlights
Bladder cancer (BCa) is one of the most common malignancies worldwide, with approximately 200,000 death and 550,000 new cases yearly (Bray et al, 2018)
We show that Mettl3 facilitates BCa progression by mediating tumor angiogenesis in vivo using transgenic mouse model
The global transcriptome sequencing with Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis reveals that Mettl3 is closely related to tumor angiogenesis
Summary
Bladder cancer (BCa) is one of the most common malignancies worldwide, with approximately 200,000 death and 550,000 new cases yearly (Bray et al, 2018). Patients with primary tumor could be treated by surgical resection, but it is limited by the several major progressions like metastasis and recurrence (Griffiths and Action on Bladder Cancer, 2013; Crabb and Douglas, 2018). Despite great efforts on larger range of novel therapies for advanced BCa, limited clinical efficacy is obtained A deeper understanding of specific mechanism in BCa metastasis and recurrence as well as the exploration of effective targets for better disease control has become major goals to be attained. Previous studies have demonstrated that Mettl3-mediated m6A modification directly regulates AFF4/NF-κB/MYC signaling network and ITGA6 mRNA, promoting BCa progression (Cheng et al, 2019; Jin et al, 2019). The understanding of the molecular mechanism of m6A in BCa in vivo remains largely undefined
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