Abstract 6980: GOLGA7 is essential for NRAS trafficking from the Golgi to the plasma membrane but not for its palmitoylation

Abstract

Abstract RAS GTPases play a crucial role as oncogenic drivers in multiple cancer types. Targeting their localization to the plasma membrane (PM) is a promising strategy for cancer therapy, as RAS signaling requires PM localization. While KRAS traffics through a Golgi-independent route, palmitoylated RAS isoforms are transported to PM from the Golgi via a secretory pathway that is not yet fully understood. GOLGA7 is a Golgi-resident protein known as an accessory protein stabilizing the palmitoyltransferase ZDHHC9 for the palmitoylation of NRAS and HRAS. In this study, we found that among all four RAS isoforms, NRAS uniquely requires GOLGA7 for its association with the PM. Interestingly, the mislocalization of NRAS is achieved without detectable changes in its palmitoylation level in GOLGA7 deficient cells. We further observed that loss of GOLGA7 inhibit the anterograde trafficking of GFP-NRASG12D proteins and result in the accumulation of NRAS in the cis compartment of the Golgi apparatus. Moreover, targeting GOLGA7 suppresses cell proliferation by downregulating RAS signaling in a variety of NRAS-mutant cancer cells. Finally, GOLGA7 depletion attenuated the oncogenic transformation induced by NRASG12D in mice. These findings reveal a specific intracellular trafficking route mediated by GOLGA7 and have identified GOLGA7 as a potential therapeutic target for NRAS-driven cancers. Citation Format: Chenxuan Liu, Bo Jiao, Peihong Wang, Baoyuan Zhang, Jiaming Gao, Donghe Li, Xi Xie, Yunying Yao, Lei Yan, Zhenghong Qin, Ping Liu, Ruibao Ren. GOLGA7 is essential for NRAS trafficking from the Golgi to the plasma membrane but not for its palmitoylation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6980.