PIASy antagonizes Ras-driven NSCLC survival by promoting GATA2 SUMOylation.

GATA2 regulated transcriptional network has been validated requisite for RAS oncogene-driven non-small cell lung cancer (NSCLC). GATA2 has been reported as a SUMOylated protein. In endothelial cells, its transcriptional activity is attenuated by SUMO-2 conjugation, which is specifically catalyzed by its E3 ligase PIASy. In this study, we found a decreased expression of PIASy in RAS mutant NSCLC cell lines and specimens with RAS mutations. Forced expression of PIASy in NSCLC cells inhibits their viability in vitro, as well as tumorigenesis and growth in vivo. Mechanistically, we demonstrated overexpression of PIASy in A549 cells altered the regulated transcriptional network of GATA2, including proteasome, IL-1-signaling, and Rho-signaling pathways. Forced expression of PIASy resulted in the accumulated SUMOylation of GATA2, attenuating its transcriptional activity in A549 cells. These results collectively suggest that PIASy plays an antagonistic role in RAS-driven NSCLC survival, by enhancing the SUMOylation of GATA2 and inhibiting its transcriptional activity.