Methyltransferase-like 14 suppresses growth and metastasis of renal cell carcinoma by decreasing long noncoding RNA NEAT1.

Growing evidence supports that N6-methyladenosine (m6A) modification acts as a critical regulator involved in tumorigenesis at the mRNA level. However, the role of m6A modification at the noncoding RNA level remains largely unknown. We found that methyltransferase-like 14 (METTL14) was significantly downregulated in renal cell carcinoma (RCC) tissues (n = 580). Gain-of-function and loss-of-function experiments revealed that METTL14 attenuated the proliferation and migration ability of RCC cells in vivo and in vitro. The methylated RNA immunoprecipitation experiments identified that METTL14 decreased the expression of long noncoding RNA nuclear enriched abundant transcript 1_1 (NEAT1_1) in an m6A-dependent manner. Mechanistically, RNA pull-down assay and RNA immunoprecipitation identified NEAT1_1 directly bound to m6A reader YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Notably, YTHDF2 accelerated the degradation of NEAT1_1 by selectively recognizing METTL14-mediated m6A marks on NEAT1_1. Multivariate analysis suggested that METTL14 downregulation was associated with malignant characteristics and predicted poor prognosis in RCC patients. In conclusion, our results uncover a newly identified METTL14-YTHDF2-NEAT1_1 signaling axis, which facilitates RCC growth and metastasis and provides fresh insight into RCC therapy.

Liu T ，Wang H ，Fu Z ，Wang Z ，Wang J ，Gan X ，Wang A ，Wang L ... -  《-》

METTL14-mediated N(6)-methyladenosine modification of ITGB4 mRNA inhibits metastasis of clear cell renal cell carcinoma.

Integrin β4 (ITGB4) participates in tumorigenesis and progression of several malignancies, but its role and related mechanisms in clear cell renal cell carcinoma (ccRCC) remain unclear. Quantitative real-time PCR (qRT-PCR), western blot and immunohistochemistry were used to detect mRNA and protein levels of relevant genes. Biological functions of ITGB4 and methyltransferase-like 14 (METTL14) were determined by in vitro and in vivo experiments. The levels of N6-methyladenosine (m6A) in ccRCC tissues and adjacent normal tissues were calculated via total RNA m6A quantification assay. The m6A modification of ITGB4 was demonstrated via m6A RNA immunoprecipitation (MeRIP), RIP and luciferase reporter assays. ITGB4 was significantly overexpressed in ccRCC tissues and high level of ITGB4 predicted poor prognosis as well as metastasis. Functionally, ITGB4 stimulated ccRCC cell migration and invasion in vitro and metastasis in vivo with epithelial-mesenchymal transition (EMT) strengthened. Mechanically, the total levels of m6A were reduced in ccRCC tissues. METTL14, a favorable factor for ccRCC patients' prognosis, facilitated m6A modification on ITGB4 3'UTR and subsequently accelerated ITGB4 mRNA degradation, leading to its declined expression. Furthermore, the METTL14-mediated inhibition of ITGB4 expression was dependent on the YTH domain family protein 2 (YTHDF2), which acted as an m6A reader to bind to ITGB4 mRNA and to promote its decay. In addition, we demonstrated that knockdown of METTL14 promoted ccRCC cell migration, invasiveness and metastasis as well as stimulating the EMT process and the PI3K/AKT signal by overexpressing ITGB4. Our study reveals that METTL14 inhibits ITGB4 expression via m6A modification to attenuate metastasis and EMT of ccRCC cells, suggesting the METTL14/ITGB4 axis as a potential prognostic biomarker and therapeutic target for ccRCC. Video Abstract.

Liu Z ，Sun T ，Piao C ，Zhang Z ，Kong C ... -  《Cell Communication and Signaling》

METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer.

Chen X ，Xu M ，Xu X ，Zeng K ，Liu X ，Pan B ，Li C ，Sun L ，Qin J ，Xu T ，He B ，Pan Y ，Sun H ，Wang S ... -  《Molecular Cancer》

METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST.

Yang X ，Zhang S ，He C ，Xue P ，Zhang L ，He Z ，Zang L ，Feng B ，Sun J ，Zheng M ... -  《Molecular Cancer》

N(6)-adenosine-methyltransferase-14 promotes glioma tumorigenesis by repressing argininosuccinate synthase 1 expression in an m6A-dependent manner.

Miao YQ ，Chen W ，Zhou J ，Shen Q ，Sun Y ，Li T ，Wang SC ... -  《-》