ARHGEF3 regulates the stability of ACLY to promote the proliferation of lung cancer

Rho GTPases play an essential role in many cellular processes, including cell cycle progress, cell motility, invasion, migration, and transformation. Several studies indicated that the dysregulation of Rho GTPase signaling is closely related to tumorigenesis. Rho GEFs considered being positive regulators of Rho GTPase, promoting the dissociation of Rho protein from GDP and binding to GTP, thus activating the downstream signaling pathway. Herein, we demonstrated that ARHGEF3, a member of the Rho GEFs family, played an important role in non-small cell lung cancer (NSCLC). We found that ARHGEF3 was highly expressed in non-small cell lung cancer and facilitated cancer cell proliferation of NSCLC cells in vitro and in vivo. Further studies demonstrated that ARHGEF3 enhanced the protein homeostasis of ATP-citrate lyase (ACLY) by reducing its acetylation on Lys17 and Lys86, leading to the dissociation between ACLY and its E3 ligase-NEDD4. Interestingly, this function of ARHGEF3 on the protein homeostasis of ACLY was independent of its GEF activity. Taken together, our findings uncover a novel function of ARHGEF3, suggesting that ARHGEF3 is a promising therapeutic target in non-small cell lung cancer.