Downregulation of m6A writer complex member METTL14 in bladder urothelial carcinoma suppresses tumor aggressiveness

• Published in: Molecular oncology 2022-05, Vol.16 (9), p.1841-1856
• Main Authors: Guimarães‐Teixeira, Catarina, Lobo, João, Miranda‐Gonçalves, Vera, Barros‐Silva, Daniela, Martins‐Lima, Cláudia, Monteiro‐Reis, Sara, Sequeira, José Pedro, Carneiro, Isa, Correia, Margareta P., Henrique, Rui, Jerónimo, Carmen
• Format: Article
• Language: English
• Subjects: Adenosine; Antibodies; Apoptosis; Bladder cancer; Cell migration; Committees; epitranscriptome; Gene expression; Genomes; Health aspects; Immunoglobulins; m6A‐regulators proteins; Methylene blue; Methyltransferase; Methyltransferases; METTL14; N6-methyladenosine; Proteins; Regulatory proteins; RNA modifications; Therapeutic targets; Tumorigenesis; Tumors; Urothelial carcinoma; Urothelium
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.13181

N6‐methyladenosine (m6A) and its regulatory proteins have been associated with tumorigenesis in several cancer types. However, knowledge on the mechanistic network related to m6A in bladder cancer (BlCa) is rather limited, requiring further investigation of its functional role. We aimed to uncover the biological role of m6A and related proteins in BlCa and understand how this influences tumor aggressiveness. N6‐adenosine‐methyltransferase catalytic subunit (METTL3), N6‐adenosine‐methyltransferase noncatalytic subunit (METTL14), protein virilizer homolog (VIRMA), and RNA demethylase ALKBH5 (ALKBH5) had significantly lower expression levels in BlCa compared to that in normal urothelium. METTL14 knockdown led to disruption of the remaining methyltransferase complex and a decrease in m6A abundance, as well as overall reduced tumor aggressiveness (decreased cell invasion and migration capacity and increased apoptosis). Furthermore, in vivo, METTL14 knockdown caused tumor size reduction. Collectively, we propose methyltransferase METTL14 as a key component for m6A RNA deposit and that it is closely related to BlCa progression, playing an important role in tumor aggressiveness. These data contribute to a better understanding of the m6A writer complex, which might constitute an appealing therapeutic target. We identified several N6‐methyladenosine (m6A)‐regulator proteins dysregulated in bladder cancer (BlCa). METTL14 knockdown disrupted the methyltransferase complex and decreased m6A abundance, impairing tumor aggressiveness. Furthermore, chorioallantoic membrane assay revealed significant tumor size reduction after knockdown of METTL14 in vivo. Our results suggest that METTL14 is a key component for m6A RNA deposit and is implicated in BlCa progression.