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/11QQ209L-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 Goq/11 signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations.Furthermore,the palmitoylation inhibitor,2-bromopalmitate,also specifically disrupted Gaq/11 downstream signaling by interfering with the MAPK pathway and BCL2 survival pathway in GNAQ/1 1-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.

Yan Zhang;Baoyuan Zhang;Yongyun Li;Yuting Dai;Jiaoyang Li;Donghe Li;Zhizhou Xia;Jianming Zhang;Ping Liu;Ming Chen;Bo Jiao;Ruibao Ren

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;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;Department of Biology,Brandeis University,Waltham,MA 02454,USA

医学前沿

[1]Yan Zhang;Baoyuan Zhang;Yongyun Li;Yuting Dai;Jiaoyang Li;Donghe Li;Zhizhou Xia;Jianming Zhang;Ping Liu;Ming Chen;Bo Jiao;Ruibao Ren-.Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma)[J].医学前沿,2022(05):784-798

Palmitoylation,GNA11,Q209,palmitoylation,11QQ209L,Goq,bromopalmitate,Gaq

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