MICAL2 Contributes to Gastric Cancer Cell Proliferation by Promoting YAP Dephosphorylation and Nuclear Translocation.

Dynamic cytoskeletal rearrangements underlie the changes that occur during cell division in proliferating cells. MICAL2 has been reported to possess reactive oxygen species- (ROS-) generating properties and act as an important regulator of cytoskeletal dynamics. However, whether it plays a role in gastric cancer cell proliferation is not known. In the present study, we found that MICAL2 was highly expressed in gastric cancer tissues, and this high expression level was associated with carcinogenesis and poor overall survival in gastric cancer patients. The knockdown of MICAL2 led to cell cycle arrest in the S phase and attenuated cell proliferation. Concomitant with S-phase arrest, a decrease in CDK6 and cyclin D protein levels was observed. Furthermore, MICAL2 knockdown attenuated intracellular ROS generation, while MICAL2 overexpression led to a decrease in the p-YAP/YAP ratio and promoted YAP nuclear localization and cell proliferation, effects that were reversed by pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) and SOD-mimetic drug tempol. We further found that MICAL2 induced Cdc42 activation, and activated Cdc42 mediated the effect of MICAL2 on YAP dephosphorylation and nuclear translocation. Collectively, our results showed that MICAL2 has a promotive effect on gastric cancer cell proliferation through ROS generation and Cdc42 activation, both of which independently contribute to YAP dephosphorylation and its nuclear translocation.