Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in <i>GNAQ/11</i>-mutant uveal melanoma

doi:10.1007/s11684-021-0911-0

Front. Med.

2022, Vol. 16

Issue (5) : 784-798 https://doi.org/10.1007/s11684-021-0911-0

RESEARCH ARTICLE

Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma

Yan Zhang¹, Baoyuan Zhang¹, Yongyun Li², Yuting Dai¹, Jiaoyang Li¹, Donghe Li¹, Zhizhou Xia¹, Jianming Zhang¹, Ping Liu¹, Ming Chen¹, Bo Jiao¹(

), Ruibao Ren^1,³(

)

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

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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 (Gα_q/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/11^Q209L-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 Gα_q/11 signaling for cell survival and proliferation than other melanoma cells without GNAQ/11 mutations. Furthermore, the palmitoylation inhibitor, 2-bromopalmitate, also specifically disrupted Gα_q/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.

Keywords uveal melanoma mutant GNAQ/11 palmitoylation BCL2 combination target therapy

Corresponding Author(s): Bo Jiao,Ruibao Ren

Just Accepted Date: 13 May 2022 Online First Date: 24 August 2022 Issue Date: 18 November 2022

Cite this article:

Yan Zhang,Baoyuan Zhang,Yongyun Li, et al. Palmitoylation of GNAQ/11 is critical for tumor cell proliferation and survival in GNAQ/11-mutant uveal melanoma[J]. Front. Med., 2022, 16(5): 784-798.

URL:

https://academic.hep.com.cn/fmd/EN/10.1007/s11684-021-0911-0
https://academic.hep.com.cn/fmd/EN/Y2022/V16/I5/784

Fig.1 Genetic perturbation of palmitoylation sites in GNAQ/11 suppresses tumor transformation in NIH3T3 cells. (A) Morphology of cultured NIH3T3 cells stably expressing the indicated proteins as observed under light microscopy (scale bar represents 20 μm). (B) Quantification of anchorage-independent growth of NIH3T3 cells expressing the indicated proteins. Colonies were counted on day 14 to day 21 after plating in triplicate. (C) Morphology of cultured NIH3T3 cells stably expressing the indicated proteins as observed under a light microscope (scale bar represents 20 μm) after BS withdrawal for 48 h. (D) Immunoblotting of the lysates of NIH3T3 cells stably expressing GNAQ/11^WT, GNAQ/11^Q209L, and GNAQ/11 ^Q209L-CS after BS withdrawal for 30 h.

Fig.2 GNAQ/11 mutations determine the effect of Gα_q/11 signaling in UM cells. (A) Cells were transfected with shGNAQ/11 lentivirus. The cells were lysed after 72 h of infection for Western blot. shGNAQ/11-mediated knockdown of GNAQ/11 decreased p-ERK1/2 and BCL2 levels and elevated PARP cleavage in two GNAQ/11-mutant melanoma cell lines (OMM2.3 and OMM1) but not in two GNAQ/11 wild-type melanoma cell lines (Mum2B and Mel290). “NC” indicates non-targeting shRNA control; “shGNAQ/11” indicates GNAQ/11-targeting shRNA. (B) GNAQ/11 knockdown reduced the proliferation of melanoma cells containing GNAQ/11 mutations (OMM2.3 and OMM1) but not the proliferation of cell lines without mutations (Mum2B and Mel290). The cells were infected with non-targeting or GNAQ/11 shRNA lentivirus; counted and plated at equal density at 3–6 days after transfection, and measured every day after plating. *P < 0.05, ** P < 0.01, and *** P < 0.001. (C) Colony assays of the effect of GNAQ/11 knockdown on the proliferation of GNAQ/11-mutant melanoma cells (OMM2.3 and OMM1) and GNAQ/11 wild-type melanoma cells (Mum2B and Mel290) using crystal violet staining after 7–13 days.

Fig.3 Loss of GNAQ/11 palmitoylation inhibits the proliferation of GNAQ/11-dependent UM cells. (A) Western blot analysis of p-ERK, total ERKs and BCL2 levels and PARP cleavage in OMM2.3 cells expressing negative control (NC) or shGNAQ (shGNAQ-1 or shGNAQ-2) and OMM2.3-shGNAQ cells ectopically expressing HA-tagged mtGNAQ (shGNAQ-resistant GNAQ^Q209P) or GNAQ^Q209P-CS (shGNAQ-resistant GNAQ^Q209P-CS). α-Tubulin was used as the loading control. The ectopically expressed GNAQ/11 variants were detected via Western blot analysis with HA antibodies, and the total expression of GNAQ was indicated by GNAQ antibodies. (B) Western blot analysis of p-ERK, total ERK, and BCL2 levels and PARP cleavage in OMM1 cells expressing NC or shGNA11 (shGNA11-1 or shGNA11-2) and the OMM1-shGNA11 cells ectopically expressing HA-tagged GNA11^Q209L (shGNA11-resistant GNA11^Q209L) or GNA11^Q209L-CS (shGNA11-resistant GNA11^Q209L-CS). α-Tubulin was used as the loading control. (C, D) Western blot analysis of p-ERK, total ERK, and BCL2 expression and PARP cleavage in wild-type human melanoma cells expressing NC or shGNAQ (shGNAQ-1 or shGNAQ-2) and hM-shGNAQ cells ectopically overexpressing HA-tagged GNAQ^WT (shRNA-resistant GNAQ^WT) or GNAQ^WT-CS (shGNAQ-resistant GNAQ^WT-CS) in Mum2B (C) and Mel290 (D) cell lines. α-Tubulin was used as the loading control. (E) Proliferation of mutant melanoma cells (OMM2.3 and OMM1 cell lines) expressing variant constructs as indicated was plotted by CellTiter Glo assay throughout 5 days. Data are presented as mean ± SD, and P values were calculated using Student’s t-test. *P < 0.05. (F) Proliferation of wild-type melanoma cells (Mum2B and Mel290 cell lines) expressing variant constructs as indicated was plotted by CellTiter Glo assay throughout 5 days. Data are presented as mean ± SD, and P values were calculated using Student’s t-test.

Fig.4 2-BP selectively inhibits the proliferation and signaling of GNAQ/11-mutant UM cells. (A) The cell viability of three representative cell lines with or without GNAQ/11 mutations treated with various 2-BP concentrations for 72 h was measured by the CellTiter Glo assay. The right panel shows the IC50 values of 2-BP in respective cell lines. IC50 values were calculated using the GraphPad Prism software. (B) Growth curves of two representative cell lines with or without GNAQ/11 mutations treated with three different 2-BP concentrations (5, 25, and 50 μmol/L) and vehicle treatment (DMSO) for over 6 days. Cells were collected by trypsinization and counted at days 0, 2, 4, and 6 in an automated cell counter (Countstar). Error bars represent SD. (C) Western blot of lysates from two representative cell lines with or without GNAQ/11 mutations harvested at 6 h after the addition of 2-BP at six doses. (D) Western blot of lysates from two representative cell lines with or without GNAQ/11 mutations harvested at 24 h after the addition of 2-BP at six doses.

Fig.5 Elevated BCL2 expression in GNAQ/11-mutant UM cells confers sensitivity to BCL2 inhibitors. (A, B) The relationship between the expression levels of GNAQ (A) or GNA11 (B) and BCL2 in 80 UM cases was analyzed based on TCGA datasets. The transcript levels of GNAQ/11 and BCL2 are positively correlated. (C) BCL2 mRNA expression across different human cancers from TCGA RNA sequencing data. BCL2 expression was highest in UVM. (D) Cutaneous melanomas with GNAQ or GNA11 mutations in TCGA had increased BCL2 mRNA expression levels comparable to those in UMs. (E) Western blot analysis of BCL2 expression in six melanoma cells that harbor the wild-type or mutant GNAQ/11. α-Tubulin was used as the loading control. (F) Cell viability of three different melanoma cell lines with GNAQ or GNA11 mutations and three melanoma cell lines without either mutation treated with ABT-199. (G) Cell viability of three different melanoma cell lines with GNAQ or GNA11 mutations and three melanoma cell lines without either mutation treated with ABT-263.

Fig.6 2-BP synergizes with ABT-199 in treating GNAQ-dependent UM cells. (A) Cell viability of OMM2.3 and OMM1 cell lines treated with increasing doses of ABT-199 in combination with 6 different doses of 2-BP. The normalized proliferation indicates the growth percentage of cells treated for 72 h with the corresponding compound combination relative to vehicle-treated cells. (B) The CI of the data indicated the strong synergy of the combination of ABT-199 and 2-BP in OMM2.3 and OMM1 cell lines as calculated by the CompuSyn software. (C) Cell viability of Mum2B and Mel290 cell lines treated with increasing doses of ABT-199 in combination with six doses of 2-BP. The normalized proliferation indicates the growth percentage of cells treated for 72 h with the corresponding compound combination relative to vehicle-treated cells. (D) Western blot analysis of indicated proteins in OMM2.3 and OMM1 cells. Cells were treated with vehicle (DMSO), 2-BP, ABT-199, or a combination of 2-BP and ABT-199 (Comb) for 16 or 24 h.

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