JARID2 activation by NFYA promotes stemness of triple-negative breast cancer cells through the PI3K/AKT pathway

Background: This study aimed to investigate the role of Jumonji AT Rich Interacting Domain 2 (JARID2) in regulating triple-negative breast Cancer (TNBC) stemness and its mechanism.

Research design and methods: Bioinformatics analysis examined JARID2 expression, prognosis, and transcription factors. Quantitative polymerase chain reaction, western blot, and immunohistochemistry detected expression. Dual luciferase reporter gene and chromatin immunoprecipitation assays verified binding. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and colony formation assay detected viability and proliferation. Sphere formation assay detected the sphere formation efficiency. Flow cytometry detected CD44⁺/CD24^- -marked stem cells. A xenograft tumor model verified the effect of JARID2 in vivo.

Results: JARID2 and nuclear transcription factor Y subunit α (NFYA) were upregulated in TNBC tissues and positively correlated. Knockdown of JARID2 or NFYA inhibited cell stemness by inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling pathway. Enforced JARID2 expression rescued the suppressive effect of NFYA knockdown on the PI3K/Akt signaling pathway and cell stemness. Knockdown of JARID2 inhibited tumor growth and cell stemness in mice but was alleviated by concurrent overexpression of NFYA.

Conclusions: NFYA promotes TNBC cell stemness by upregulating JARID2 expression and regulating the PI3K/Akt signaling pathway, suggesting JARID2 as a potential target for innovating drugs that target TNBC stem cells.

JARID2; NFYA; PI3K/AKT signaling pathway; stemness; triple-negative breast cancer.