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

• Published in: Cell death & disease Vol. 14; no. 7; pp. 454 - 12
• Main Authors: Li, Xinru, Liu, Yan, Liu, Juan, Qiang, Wei, Ma, Jingjing, Xie, Jingyi, Chen, Pu, Wang, Yubo, Hou, Peng, Ji, Meiju
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.07.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 13; 38; 631/67/1459/1843; 631/67/2327; 64; 96; AKT protein; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; c-Myc protein; Cell Biology; Cell Culture; Cell Cycle Proteins - genetics; Cell Line, Tumor; Cell proliferation; Chromatids; Chromosomes; Glutaminase; Glutaminase - metabolism; Glutamine; Glutamine - genetics; Humans; Immunology; Life Sciences; MEK inhibitors; Melanoma; Melanoma - pathology; Metabolism; Mice; Mice, Nude; Mitogen-Activated Protein Kinase Kinases - genetics; Mitosis; Mutants; Mutation - genetics; Myc protein; Phenotypes; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins B-raf - genetics; Sister chromatids; Thyroid cancer; Thyroid Neoplasms - genetics
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-05981-z

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.