Musashi-2 (MSI2) regulation of DNA damage response in lung cancer

Abstract

AbstractLung cancer is one of the most common types of cancers worldwide. Non-small cell lung cancer (NSCLC), typically caused byKRASandTP53driver mutations, represents the majority of all new lung cancer diagnoses. Overexpression of the RNA-binding protein (RBP) Musashi-2 (MSI2) has been associated with NSCLC progression. To investigate the role of MSI2 in NSCLC development, we compared the tumorigenesis in mice with lung-specificKras-activating mutation andTrp53deletion, with and withoutMsi2deletion (KP versus KPM2 mice). KPM2 mice showed decreased lung tumorigenesis in comparison with KP mice what supports published data. In addition, using cell lines from KP and KPM2 tumors, and human NSCLC cell lines, we found that MSI2 directly bindsATM/AtmmRNA and regulates its translation. MSI2 depletion impaired DNA damage response (DDR) signaling and sensitized human and murine NSCLC cells to treatment with PARP inhibitorsin vitroandin vivo. Taken together, we conclude that MSI2 supports lung tumorigenesis, in part, by direct positive regulation of ATM protein expression and DDR. This adds the knowledge of MSI2 function in lung cancer development. Targeting MSI2 may be a promising strategy to treat lung cancer.SignificanceThis study shows the novel role of Musashi-2 as regulator of ATM expression and DDR in lung cancer.