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

Abstract

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.

Advances of E3 ligases in lung cancer

“…NEDD4 can degrade ATP citrate lyase (ACLY) through K48-linked ubiquitination, which in turn inhibits lung cancer cell proliferation [ 34 ]. NEDD4 also ubiquitinates and induces degradation of phosphorylated 3-hydroxy-3-methylglutaryl-CoA lyase (HMGCL), which will result in the promotion of proliferation and tumorigenesis in NSCLC [ 35 ].…”

Ubiquitination Links DNA Damage and Repair Signaling to Cancer Metabolism

“…For example, ACLY is ubiquitinated and subsequently degraded by E3 ligase NEDD4 in lung cancer cells and is a key metabolic enzyme that produces the acetyl-CoA required for fatty acid metabolism in cancer [113,114]. In NSCLC, the stability and activation of ACLY are enhanced by the dissociation between E3 ligase NEDD4 and ACLY, which promotes a high level of acetyl-CoA and fatty metabolism, subsequently inducing tumor proliferation [115]. ACLY also participates in DDR by promoting histone acetylation, which is important for the proper repair of DNA DSBs in response to DNA damage [116].…”