STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells.
STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells.
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DOI：
10.1038/s41419-023-05981-z
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发表时间：
2023-07-21
影响因子：
9
通讯作者：
Ji, Meiju
中科院分区：
文献类型：
--
作者：
Li, Xinru;Liu, Yan;Liu, Juan;Qiang, Wei;Ma, Jingjing;Xie, Jingyi;Chen, Pu;Wang, Yubo;Hou, Peng;Ji, Meiju
STAG 2是内聚复合体中的一个重要亚基，在有丝分裂后期参与染色体分离和姐妹染色单体的形成。STAG 2的突变失活是BRAF突变型黑色素瘤对BRAF/MEK抑制剂耐药的主要原因。在本研究中，我们发现与对照受试者相比，STAG 2在甲状腺癌中经常下调。通过一系列的体外和体内研究，我们证明，STAG 2基因敲除对BRAF突变型甲状腺癌细胞的恶性表型，如细胞增殖，集落形成和裸鼠致瘤能力与对照相比几乎没有影响。此外，与黑色素瘤不同，STAG 2敲低也不影响这些细胞对MEK抑制剂的敏感性。然而，我们惊奇地发现，与对照细胞相比，STAG 2敲低的细胞表现出对谷氨酰胺剥夺或谷氨酰胺酶抑制剂BPTES更敏感。从机制上讲，敲低BRAF突变型甲状腺癌细胞中的STAG 2通过ERK/AKT/GSK 3 β反馈途径降低了c-Myc的蛋白质稳定性，从而通过下调其下游靶点如SCL 1A 5、GLS和GLS 2来损害甲状腺癌细胞的谷氨酰胺代谢。我们的数据综合起来表明，STAG 2失活重新编程BRAF突变型甲状腺癌细胞的谷氨酰胺代谢，从而改善其对转氨酶抑制剂的细胞反应。这项研究将为BRAF突变型甲状腺癌提供一种潜在的治疗策略。
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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影响因子：
5.1
作者：
Chen, Wan-qing;Zeng, Hong-mei;He, Jie
通讯作者：
He, Jie
影响因子：
4
作者：
Kong B;Qia C;Erkan M;Kleeff J;Michalski CW
通讯作者：
Michalski CW
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影响因子：
5.8
作者：
Cui, Bo;Yang, Qi;Ji, Meiju
通讯作者：
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影响因子：
28.2
作者：
Montero-Conde C;Ruiz-Llorente S;Dominguez JM;Knauf JA;Viale A;Sherman EJ;Ryder M;Ghossein RA;Rosen N;Fagin JA
通讯作者：
Fagin JA
影响因子：
5.6
作者：
Chen L;Cui H
通讯作者：
Cui H