m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC

Abstract

Background: The 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. Methods: Protein 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 m 6 A modification was analyzed by MeRIP. Results: Our 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 m 6 A modification of YAP. YTHDF3 combined YAP pre-mRNA depending on m 6 A modification. YTHDF1 and YTHDF2 competitively interacted with YTHDF3 in an m 6 A-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 m 6 A 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. Conclusions: The presented findings suggest m 6 A 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 m 6 A modification of ALKBH5 might constitute a potential treatment strategy for lung cancer.

<p>Construction and Validation of an m6A RNA Methylation Regulators-Based Prognostic Signature for Esophageal Cancer</p>

“…Another study by Jin et al suggested that ALKBH5 inhibited tumor growth and metastasis in vivo by reducing the expression and activity of YAP. 17 Consistent with these studies, the results of our study showed that ALKBH5 is underexpressed in ESCA tissues, and low expression of ALKBH5 was associated with poor survival, indicating that ALKBH5 might act as a tumor suppressor gene in ESCA.…”

ALKBH5 suppresses malignancy of hepatocellular carcinoma via m6A-guided epigenetic inhibition of LYPD1

“…However, Tang et al uncover the tumor suppressive function of ALKBH5 through m 6 A-dependent inactivation of Wnt signaling [34]. In addition, ALKBH5 inhibits tumor growth and metastasis via abolishing expression and activity of YAP in non-small cell lung cancer [35]. And our findings also clarify that ALKBH5 inhibits HCC malignancy through impairing the expression of LYPD1.…”

Downregulation of m6A reader YTHDC2 promotes tumor progression and predicts poor prognosis in non‐small cell lung cancer

“…For example, m 6 A demethylase ALKBH5 (m 6 A eraser) has been shown to inhibit tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibit miR-107/ LATS2-mediated YAP activity in NSCLC. 21 Another m 6 A methyladenosine METTL3 (m 6 A writer) induced miR-143-3p has been reported to promote the brain metastasis of lung cancer via regulation of VASH1. 22 In addition, Liu et al demonstrated that m 6 A demethylase FTO (m 6 A eraser) promotes cell proliferation and invasion in lung squamous cell carcinoma by regulating MZF1 expression.…”