Chaperonin‐containing TCP1 subunit 6A inhibition via TRIM21‐mediated K48‐linked ubiquitination suppresses triple‐negative breast cancer progression through the AKT signalling pathway

作者：Mengdi Yang, Jianing Cao, Tiantian Liu, Bin Li, Jinyan Wang, S L Pan, Duancheng Guo, Zhonghua Tao, Xichun Hu · 发表于：Clinical and Translational Medicine · 年份：2024 · DOI：10.1002/ctm2.70097 · 被引用次数：9 · 研究领域：Heat shock proteins research、FOXO transcription factor regulation、interferon and immune responses

BACKGROUND: Triple-negative breast cancer (TNBC) is distinguished by a significant likelihood of distant recurrence and an unfavourable prognosis. However, the underlying molecules and mechanisms have not been fully elucidated. METHODS: We investigated the expression profile and clinical relevance of chaperonin-containing TCP1 subunit 6A (CCT6A) in TNBC. We performed cell function assays on TNBC cells with CCT6A knockdown or overexpression. To further explore the mechanism of action of CCT6A, RNA sequencing and co-immunoprecipitation-mass spectrometry analyses were utilized. Rescue and ubiquitination assays evaluated the impact of TRIM21-mediated CCT6A ubiquitination and degradation on TNBC progression in vitro and in vivo. Finally, we studied the potential of Ipatasertib, a pharmacological AKT inhibitor, and/or anti-PD1 therapy in inhibiting TNBC progression. RESULTS: Elevated CCT6A expression in TNBC patients was associated with an adverse prognosis and lymph node metastasis. Mechanistically, CCT6A facilitated cell migration, invasion, epithelial-mesenchymal transition and proliferation by activating the phosphatidylinositol 3-kinase (PI3K)/AKT pathway. The TRIM21 RING domain is an E3 ligase, facilitating the K48-linked ubiquitination-mediated degradation of CCT6A, thereby impeding TNBC progression. Moreover, in the tumour tissues of the CCT6A-overexpressing mice, the quantity of CD8+ T cells and the concentration of secreted interferon-gamma were decreased, whereas in the ...