Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma.
10.1007/s11684-021-0911-0
- Author:
Yan ZHANG
1
;
Baoyuan ZHANG
1
;
Yongyun LI
2
;
Yuting DAI
1
;
Jiaoyang LI
1
;
Donghe LI
1
;
Zhizhou XIA
1
;
Jianming ZHANG
1
;
Ping LIU
1
;
Ming CHEN
1
;
Bo JIAO
3
;
Ruibao REN
4
Author Information
1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
2. Department of Ophthalmology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai, 200001, China.
3. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. bjiao@sibs.ac.cn.
4. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine at Shanghai, Collaborative Innovation Center of Hematology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. ren@brandeis.edu.
- Publication Type:Journal Article
- Keywords:
BCL2;
combination target therapy;
mutant GNAQ/11;
palmitoylation;
uveal melanoma
- MeSH:
Humans;
Mice;
Animals;
Lipoylation;
NIH 3T3 Cells;
Uveal Neoplasms/genetics*;
Melanoma/genetics*;
Cell Proliferation;
Proto-Oncogene Proteins c-bcl-2;
GTP-Binding Protein alpha Subunits, Gq-G11/genetics*
- From:
Frontiers of Medicine
2022;16(5):784-798
- CountryChina
- Language:English
-
Abstract:
More than 85% of patients with uveal melanoma (UM) carry a GNAQ or GNA11 mutation at a hotspot codon (Q209) that encodes G protein α subunit q/11 polypeptides (Gαq/11). GNAQ/11 relies on palmitoylation for membrane association and signal transduction. Despite the palmitoylation of GNAQ/11 was discovered long before, its implication in UM remains unclear. Here, results of palmitoylation-targeted mutagenesis and chemical interference approaches revealed that the loss of GNAQ/11 palmitoylation substantially affected tumor cell proliferation and survival in UM cells. Palmitoylation inhibition through the mutation of palmitoylation sites suppressed GNAQ/11Q209L-induced malignant transformation in NIH3T3 cells. Importantly, the palmitoylation-deficient oncogenic GNAQ/11 failed to rescue the cell death initiated by the knock down of endogenous GNAQ/11 oncogenes in UM cells, which are much more dependent on Gαq/11 signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations. Furthermore, the palmitoylation inhibitor, 2-bromopalmitate, also specifically disrupted Gαq/11 downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/11-mutant UM cells and showed a notable synergistic effect when applied in combination with the BCL2 inhibitor, ABT-199, in vitro. The findings validate that GNAQ/11 palmitoylation plays a critical role in UM and may serve as a promising therapeutic target for GNAQ/11-driven UM.
