Author:
Liu Chenxuan,Jiao Bo,Wang Peihong,Zhang Baoyuan,Gao Jiaming,Li Donghe,Xie Xi,Yao Yunying,Yan Lei,Qin Zhenghong,Liu Ping,Ren Ruibao
Abstract
AbstractNRAS mutations are most frequently observed in hematological malignancies and are also common in some solid tumors such as melanoma and colon cancer. Despite its pivotal role in oncogenesis, no effective therapies targeting NRAS has been developed. Targeting NRAS localization to the plasma membrane (PM) is a promising strategy for cancer therapy, as its signaling requires PM localization. However, the process governing NRAS translocation from the Golgi apparatus to the PM after lipid modification remains elusive. This study identifies GOLGA7 as a crucial factor controlling NRAS’ PM translocation, demonstrating that its depletion blocks NRAS, but not HRAS, KRAS4A and KRAS4B, translocating to PM. GOLGA7 is known to stabilize the palmitoyltransferase ZDHHC9 for NRAS and HRAS palmitoylation, but we found that GOLGA7 depletion does not affect NRAS’ palmitoylation level. Further studies show that loss of GOLGA7 disrupts NRAS anterograde trafficking, leading to its cis-Golgi accumulation. Remarkably, depleting GOLGA7 effectively inhibits cell proliferation in multiple NRAS-mutant cancer cell lines and attenuates NRASG12D-induced oncogenic transformation in vivo. These findings elucidate a specific intracellular trafficking route for NRAS under GOLGA7 regulation, highlighting GOLGA7 as a promising therapeutic target for NRAS-driven cancers.
Funder
the Key Project of National Natural Science Foundation of China
Shanghai Pujiang Program
the Innovative Research Team of High-level Local Universities in Shanghai
Shanghai Science and Technology Development Funds
Shanghai Collaborative Innovation Program on Regenerative Medicine and Stem Cell Research
the Samuel Waxman Cancer Research Foundation
Publisher
Springer Science and Business Media LLC
Subject
Cell Biology,Molecular Biology,Biochemistry