STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells

STAG2, an important subunit in cohesion complex, is involved in the segregation of chromosomes during the late mitosis and the formation of sister chromatids. Mutational inactivation of STAG2 is a major cause of the resistance of BRAF-mutant melanomas to BRAF/MEK inhibitors. In the present study, we...

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Autores principales: Li, Xinru, Liu, Yan, Liu, Juan, Qiang, Wei, Ma, Jingjing, Xie, Jingyi, Chen, Pu, Wang, Yubo, Hou, Peng, Ji, Meiju
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361981/
https://www.ncbi.nlm.nih.gov/pubmed/37479689
http://dx.doi.org/10.1038/s41419-023-05981-z
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author Li, Xinru
Liu, Yan
Liu, Juan
Qiang, Wei
Ma, Jingjing
Xie, Jingyi
Chen, Pu
Wang, Yubo
Hou, Peng
Ji, Meiju
author_facet Li, Xinru
Liu, Yan
Liu, Juan
Qiang, Wei
Ma, Jingjing
Xie, Jingyi
Chen, Pu
Wang, Yubo
Hou, Peng
Ji, Meiju
author_sort Li, Xinru
collection PubMed
description STAG2, an important subunit in cohesion complex, is involved in the segregation of chromosomes during the late mitosis and the formation of sister chromatids. Mutational inactivation of STAG2 is a major cause of the resistance of BRAF-mutant melanomas to BRAF/MEK inhibitors. In the present study, we found that STAG2 was frequently down-regulated in thyroid cancers compared with control subjects. By a series of in vitro and in vivo studies, we demonstrated that STAG2 knockdown virtually had no effect on malignant phenotypes of BRAF-mutant thyroid cancer cells such as cell proliferation, colony formation and tumorigenic ability in nude mice compared with the control. In addition, unlike melanoma, STAG2 knockdown also did not affect the sensitivity of these cells to MEK inhibitor. However, we surprisingly found that STAG2-knockdown cells exhibited more sensitive to glutamine deprivation or glutaminase inhibitor BPTES compared with control cells. Mechanistically, knocking down STAG2 in BRAF-mutant thyroid cancer cells decreases the protein stability of c-Myc via the ERK/AKT/GSK3β feedback pathway, thereby impairing glutamine metabolism of thyroid cancer cells by down-regulating its downstream targets such as SCL1A5, GLS and GLS2. Our data, taken together, demonstrate that STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells, thereby improving their cellular response to glutaminase inhibitor. This study will provide a potential therapeutic strategy for BRAF-mutant thyroid cancers.
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spelling pubmed-103619812023-07-23 STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells Li, Xinru Liu, Yan Liu, Juan Qiang, Wei Ma, Jingjing Xie, Jingyi Chen, Pu Wang, Yubo Hou, Peng Ji, Meiju Cell Death Dis Article STAG2, an important subunit in cohesion complex, is involved in the segregation of chromosomes during the late mitosis and the formation of sister chromatids. Mutational inactivation of STAG2 is a major cause of the resistance of BRAF-mutant melanomas to BRAF/MEK inhibitors. In the present study, we found that STAG2 was frequently down-regulated in thyroid cancers compared with control subjects. By a series of in vitro and in vivo studies, we demonstrated that STAG2 knockdown virtually had no effect on malignant phenotypes of BRAF-mutant thyroid cancer cells such as cell proliferation, colony formation and tumorigenic ability in nude mice compared with the control. In addition, unlike melanoma, STAG2 knockdown also did not affect the sensitivity of these cells to MEK inhibitor. However, we surprisingly found that STAG2-knockdown cells exhibited more sensitive to glutamine deprivation or glutaminase inhibitor BPTES compared with control cells. Mechanistically, knocking down STAG2 in BRAF-mutant thyroid cancer cells decreases the protein stability of c-Myc via the ERK/AKT/GSK3β feedback pathway, thereby impairing glutamine metabolism of thyroid cancer cells by down-regulating its downstream targets such as SCL1A5, GLS and GLS2. Our data, taken together, demonstrate that STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells, thereby improving their cellular response to glutaminase inhibitor. This study will provide a potential therapeutic strategy for BRAF-mutant thyroid cancers. Nature Publishing Group UK 2023-07-21 /pmc/articles/PMC10361981/ /pubmed/37479689 http://dx.doi.org/10.1038/s41419-023-05981-z Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Li, Xinru
Liu, Yan
Liu, Juan
Qiang, Wei
Ma, Jingjing
Xie, Jingyi
Chen, Pu
Wang, Yubo
Hou, Peng
Ji, Meiju
STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells
title STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells
title_full STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells
title_fullStr STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells
title_full_unstemmed STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells
title_short STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells
title_sort stag2 inactivation reprograms glutamine metabolism of braf-mutant thyroid cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10361981/
https://www.ncbi.nlm.nih.gov/pubmed/37479689
http://dx.doi.org/10.1038/s41419-023-05981-z
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