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Published on: August 23, 2019
STAG2 inactivation reprograms glutamine metabolism of BRAF-mutant thyroid cancer cells
Xinru Li1,2, Yan Liu1, Juan Liu1
1Key Laboratory for Tumor Precision Medicine of Shaanxi Province and Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
Abstract:
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.
Insights
STAG2 down-regulation in thyroid cancer does not affect BRAF-mutant cell proliferation but enhances sensitivity to glutamine deprivation. This occurs by decreasing c-Myc stability, impairing glutamine metabolism and offering a new therapeutic strategy.
Area of Science:
- Oncology
- Cell Biology
- Molecular Biology
Background:
- STAG2 is a key subunit of the cohesion complex, crucial for chromosome segregation.
- Mutational inactivation of STAG2 contributes to BRAF/MEK inhibitor resistance in melanomas.
- STAG2 is frequently down-regulated in thyroid cancers.
Purpose of the Study:
- To investigate the role of STAG2 in BRAF-mutant thyroid cancer.
- To explore the effect of STAG2 knockdown on thyroid cancer cell phenotypes and drug sensitivity.
- To elucidate the underlying mechanisms of STAG2's function in thyroid cancer metabolism.
Main Methods:
- In vitro and in vivo studies including STAG2 knockdown experiments.
- Assessment of cell proliferation, colony formation, and tumorigenic ability.
- Analysis of sensitivity to MEK inhibitors, glutamine deprivation, and glutaminase inhibitors (BPTES).
- Investigation of c-Myc protein stability and downstream metabolic targets (SCL1A5, GLS, GLS2) via the ERK/AKT/GSK3β pathway.
Main Results:
- STAG2 knockdown did not significantly affect proliferation, colony formation, or tumorigenicity of BRAF-mutant thyroid cancer cells.
- STAG2 knockdown did not alter sensitivity to MEK inhibitors in these cells.
- STAG2-knockdown cells showed increased sensitivity to glutamine deprivation and the glutaminase inhibitor BPTES.
- STAG2 knockdown reduced c-Myc protein stability, impairing glutamine metabolism by down-regulating SCL1A5, GLS, and GLS2.
Conclusions:
- STAG2 inactivation reprograms glutamine metabolism in BRAF-mutant thyroid cancer cells.
- This reprogramming enhances cellular response to glutaminase inhibitors.
- Targeting glutamine metabolism represents a potential therapeutic strategy for BRAF-mutant thyroid cancers.
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