Abstract
BackgroundThe importance of mRNA methylation erased by ALKBH5 in mRNA biogenesis, decay, and translation control is an emerging research focus. Ectopically activated YAP is associated with the development of many human cancers. However, the mechanism whereby ALKBH5 regulates YAP expression and activity to inhibit NSCLC tumor growth and metastasis is not clear.MethodsProtein and transcript interactions were analyzed in normal lung cell and NSCLC cells. Gene expression was evaluated by qPCR and reporter assays. Protein levels were determined by immunochemical approaches. Nucleic acid interactions and status were analyzed by immunoprecipitation. Cell behavior was analyzed by standard biochemical tests. The m6A modification was analyzed by MeRIP.ResultsOur results show that YAP expression is negatively correlated with ALKBH5 expression and plays an opposite role in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. ALKBH5 reduced m6A modification of YAP. YTHDF3 combined YAP pre-mRNA depending on m6A modification. YTHDF1 and YTHDF2 competitively interacted with YTHDF3 in an m6A-independent manner to regulate YAP expression. YTHDF2 facilitated YAP mRNA decay via the AGO2 system, whereas YTHDF1 promoted YAP mRNA translation by interacting with eIF3a; both these activities are regulated by m6A modification. Furthermore, ALKBH5 decreased YAP activity by regulating miR-107/LATS2 axis in an HuR-dependent manner. Further, ALKBH5 inhibited tumor growth and metastasis in vivo by reducing the expression and activity of YAP.ConclusionsThe presented findings suggest m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC. Moreover, effective inhibition of m6A modification of ALKBH5 might constitute a potential treatment strategy for lung cancer.
Highlights
The importance of mRNA methylation erased by AlkB homolog 5 (ALKBH5) in mRNA biogenesis, decay, and translation control is an emerging research focus
Using lung healthy cells and tumor cells, we demonstrated the following: (1) ALKBH5 decreases the level of m6A YAP mRNA modification; (2) YTHDF1 and YTHDF2 competitively bind YTHDF3 in an m6A-independent manner to regulate YAP expression; (3) YTHDF2 facilitates the decay of YAP mRNA, which is mediated by Argonaute 2 (AGO2)
We found that YAP expression was negatively correlated with ALKBH5 expression in Non-small cell lung cancer (NSCLC) tumor tissues (Table 1)
Summary
The importance of mRNA methylation erased by ALKBH5 in mRNA biogenesis, decay, and translation control is an emerging research focus. The mechanism whereby ALKBH5 regulates YAP expression and activity to inhibit NSCLC tumor growth and metastasis is not clear. Reversible RNA modification constitutes a new level of post-transcriptional regulation of gene expression, involved in many physiological processes and with multiple biological roles [3]. ALKBH5 holds prognostic value and inhibits the metastasis of colon cancer [8]; ALKBH5 controls trophoblast invasion at the maternal-fetal interface by regulating the stability of Cyr mRNA [9]; METTL3 and ALKBH5 oppositely regulate m6A modification of TFEB mRNA, dictating the fate of hypoxia/reoxygenation-treated cardiomyocyte [10]; ALKBH5 inhibits pancreatic cancer cell motility by decreasing methylation of the long non-coding RNA KCNK15-AS1 [11]. The mechanism through which ALKBH5 regulates NSCLC tumor growth and metastasis is not clear
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