ALKBH5-dependent upregulation of circARHGEF12 by Oridonin impairs gastric cancer progression and cisplatin resistance via regulating miR-130b-5p/LATS2 signaling

Background Accumulating evidence unveils that N6-methyladenosine (m ⁶ A) methylation modifications and deregulated circular RNAs (circRNAs) play critical roles in diverse malignancies including gastric cancer (GC). However, the underlying mechanisms by which ALKBH5 mediates m ⁶ A modification of circRNAs in GC progression and chemoresistance remain unknown. Methods The m ⁶ A-circRNA epi-transcriptomic microarray was applied to screen ALKBH5-mediated m ⁶ A demethylation of hsa_circ_0002089 (circARHGEF12), which was verified by m ⁶ A dot blot, RT-qPCR, methylated RNA immunoprecipitation (Me-RIP) and RIP assays. The cellular localization and mRNA expression levels of circARHGEF12 in GC tissue samples were detected by fluorescence in situ hybridization. Gain- or loss-of-function assays as well as in vivo tumorigenesis and lung metastasis models were executed to assess the role of circARHGEF12 in GC cells. The specific binding of circARHGEF12 with miR-130b-5p was validated by RT-qPCR, RIP, and luciferase gene report assays. The effects of Oridonin-mediated ALKBH5 and (or) circARHGEF12 on miR-130b-5p/LATS2/YAP signaling were determined by RT-qPCR, Western blot and functional assays. Results We found that circARHGEF12 was identified as an m ⁶ A-modified target of ALKBH5 in GC cells. Overexpression of circARHGEF12 impaired cell proliferation and cisplatin resistance in vitro as well as repressed gastric tumorigenesis and lung metastasis in vivo , but circARHGEF12 knockdown (KD) drove these effects. Furthermore, circARHGEF12 could act as the sponge of miR-130b-5p to attenuate ALKBH5 KD-induced miR-130b-5p upregulation and LATS2/YAP inactivation in GC cells. Oridonin activates ALKBH5 to enhances GC suppression via miR-130b-5p/LATS2 signaling. Conclusion Our findings reveal that ALKBH5-dependent upregulation of circARHGEF12 by oridonin impairs GC progression and cisplatin resistance via regulating miR-130b-5p/LATS2 signaling and may provide a novel therapeutic target for GC.