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GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner

GNA13, encoding one of the G protein alpha subunits of heterotrimeric G proteins that transduce signals of G protein-coupled receptors (GPCR), is frequently mutated in germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) with poor prognostic outcomes. Due to the “undruggable” nature...

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Autores principales: Xia, Zhizhou, Zhang, Xiuli, Liu, Ping, Zhang, Ruihong, Huang, Zhangsen, Li, Donghe, Xiao, Xinhua, Wu, Min, Ning, Nannan, Zhang, Qianqian, Zhang, Jianmin, Liu, Mingzhu, Jiao, Bo, Ren, Ruibao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797003/
https://www.ncbi.nlm.nih.gov/pubmed/33423045
http://dx.doi.org/10.1038/s41419-020-03311-1
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author Xia, Zhizhou
Zhang, Xiuli
Liu, Ping
Zhang, Ruihong
Huang, Zhangsen
Li, Donghe
Xiao, Xinhua
Wu, Min
Ning, Nannan
Zhang, Qianqian
Zhang, Jianmin
Liu, Mingzhu
Jiao, Bo
Ren, Ruibao
author_facet Xia, Zhizhou
Zhang, Xiuli
Liu, Ping
Zhang, Ruihong
Huang, Zhangsen
Li, Donghe
Xiao, Xinhua
Wu, Min
Ning, Nannan
Zhang, Qianqian
Zhang, Jianmin
Liu, Mingzhu
Jiao, Bo
Ren, Ruibao
author_sort Xia, Zhizhou
collection PubMed
description GNA13, encoding one of the G protein alpha subunits of heterotrimeric G proteins that transduce signals of G protein-coupled receptors (GPCR), is frequently mutated in germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) with poor prognostic outcomes. Due to the “undruggable” nature of GNA13, targeted therapy for these patients is not available. In this study, we found that palmitoylation of GNA13 not only regulates its plasma membrane localization, but also regulates GNA13’s stability. It is essential for the tumor suppressor function of GNA13 in GCB-DLBCL cells. Interestingly, GNA13 negatively regulates BCL2 expression in GCB-DLBCL cells in a palmitoylation-dependent manner. Consistently, BCL2 inhibitors were found to be effective in killing GNA13-deficient GCB-DLBCL cells in a cell-based chemical screen. Furthermore, we demonstrate that inactivating GNA13 by targeting its palmitoylation enhanced the sensitivity of GCB-DLBCL to the BCL2 inhibitor. These studies indicate that the loss-of-function mutation of GNA13 is a biomarker for BCL2 inhibitor therapy of GCB-DLBCL and that GNA13 palmitoylation is a potential target for combination therapy with BCL2 inhibitors to treat GCB-DLBCL with wild-type GNA13.
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spelling pubmed-77970032021-01-21 GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner Xia, Zhizhou Zhang, Xiuli Liu, Ping Zhang, Ruihong Huang, Zhangsen Li, Donghe Xiao, Xinhua Wu, Min Ning, Nannan Zhang, Qianqian Zhang, Jianmin Liu, Mingzhu Jiao, Bo Ren, Ruibao Cell Death Dis Article GNA13, encoding one of the G protein alpha subunits of heterotrimeric G proteins that transduce signals of G protein-coupled receptors (GPCR), is frequently mutated in germinal center B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) with poor prognostic outcomes. Due to the “undruggable” nature of GNA13, targeted therapy for these patients is not available. In this study, we found that palmitoylation of GNA13 not only regulates its plasma membrane localization, but also regulates GNA13’s stability. It is essential for the tumor suppressor function of GNA13 in GCB-DLBCL cells. Interestingly, GNA13 negatively regulates BCL2 expression in GCB-DLBCL cells in a palmitoylation-dependent manner. Consistently, BCL2 inhibitors were found to be effective in killing GNA13-deficient GCB-DLBCL cells in a cell-based chemical screen. Furthermore, we demonstrate that inactivating GNA13 by targeting its palmitoylation enhanced the sensitivity of GCB-DLBCL to the BCL2 inhibitor. These studies indicate that the loss-of-function mutation of GNA13 is a biomarker for BCL2 inhibitor therapy of GCB-DLBCL and that GNA13 palmitoylation is a potential target for combination therapy with BCL2 inhibitors to treat GCB-DLBCL with wild-type GNA13. Nature Publishing Group UK 2021-01-09 /pmc/articles/PMC7797003/ /pubmed/33423045 http://dx.doi.org/10.1038/s41419-020-03311-1 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Xia, Zhizhou
Zhang, Xiuli
Liu, Ping
Zhang, Ruihong
Huang, Zhangsen
Li, Donghe
Xiao, Xinhua
Wu, Min
Ning, Nannan
Zhang, Qianqian
Zhang, Jianmin
Liu, Mingzhu
Jiao, Bo
Ren, Ruibao
GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner
title GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner
title_full GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner
title_fullStr GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner
title_full_unstemmed GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner
title_short GNA13 regulates BCL2 expression and the sensitivity of GCB-DLBCL cells to BCL2 inhibitors in a palmitoylation-dependent manner
title_sort gna13 regulates bcl2 expression and the sensitivity of gcb-dlbcl cells to bcl2 inhibitors in a palmitoylation-dependent manner
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7797003/
https://www.ncbi.nlm.nih.gov/pubmed/33423045
http://dx.doi.org/10.1038/s41419-020-03311-1
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