Dysregulated BCL9 Controls Tumorigenicity and Ferroptosis Susceptibility by Binding With Nrf2 in Thyroid Carcinoma

• Published in: Molecular carcinogenesis 2024-12, Vol.63 (12), p.2382-2391
• Main Authors: Wang, Bin, Yao, Zhihao, Wang, Zhenhua, Yao, Shenzhen, Cen, Xiaoxia, Zhang, Wei
• Format: Article
• Language: English
• Subjects: Animals; BCL9; Cancer therapies; Carcinogenesis - genetics; Carcinogenesis - metabolism; Cell death; Cell Line, Tumor; Cell migration; Cell Movement; Cell Proliferation; Endocrine system; Female; Ferroptosis; Ferroptosis - genetics; Gene Expression Regulation, Neoplastic; Gene silencing; Humans; Immunoprecipitation; Lipid peroxidation; Male; Mice; Mice, Nude; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Nrf2; Thyroid cancer; Thyroid carcinoma; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Transcription Factors - genetics; Transcription Factors - metabolism; Tumorigenicity; Tumors; Xenograft Model Antitumor Assays
• ISSN: 0899-1987; 1098-2744; 1098-2744
• DOI: 10.1002/mc.23816

ABSTRACT Thyroid carcinoma (TC) is the most common malignant tumor of the endocrine system with increasing incidence. In this study, we found that BCL9 is markedly upregulated in human TC tumors and its expression is positively corrected with the process of TC. Functionally, we found that overexpression of BCL9 promoted the proliferation and migration of TC cells, while reduced the sensitivity of TC cells to ferroptosis, a form of cell death driven by iron‐dependent lipid peroxidation and implicated as a novel cancer therapeutic strategy. Mechanistically, the co‐immunoprecipitation assay determined that BCL9 could bind to Nrf2 which has been confirmed to play an important role in ferroptosis. Furthermore, we demonstrated that silence of BCL9 could decrease Nrf2 expression, and then affect the expression of the downstream genes of Nrf2, ultimately induce ferroptosis. Importantly, we confirmed the effects of BCL9 on TC tumors in vivo. Overall, this study unveils the functional role and clinical significance of BCL9 in TC progression, and highlights the potential of targeting BCL9/Nrf2 ferroptosis axis as a novel therapeutic strategy for TC treatment.