Deficiency of Mettl3 in Bladder Cancer Stem Cells Inhibits Bladder Cancer Progression and Angiogenesis

Frontiers in Cell and Developmental Biology

Jianwen Chen¹  Zhi Chen¹  Maosheng Cheng¹  Kang Li¹  Xiaochen Wang¹  Shuang Chen¹  Demeng Chen¹  Ganping Wang¹  Liang Peng²  Gan Xiong³  Xiuyun Xu³  Yarong Dai⁴  Rong-song Ling⁴ 

[1] Center for Translational Medicine, Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China;Department of Oncology, Chinese PLA General Hospital, Beijing, China;Department of Oral and Maxillofacial Surgery, Hospital of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou, China;Institute for Advanced Study, Shenzhen University, Shenzhen, China;

关键词: Mettl3;    cancer stem cell;    bladder cancer;    m6A;    angiogenesis;   

DOI  :  10.3389/fcell.2021.627706

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown