JARID2 promotes prostate cancer progression associated with TET3-mediated activation of the FAK/PI3K/AKT signaling pathway

JARID2, a regulatory Polycomb Repressive Complex 2 (PRC2) component, has diverse roles in cancer development, yet its function in prostate cancer (PCa) remains unclear. We analyzed JARID2 expression using TCGA-PRAD data and clinical samples. Functional assays, including CCK-8, wound healing, and Transwell assays, were conducted to assess the influence of JARID2 overexpression or knockdown in PCa cell lines. The JARID2-TET3 interaction was validated by co-immunoprecipitation, and rescue experiments were performed to evaluate TET3’s functional role. Pathway enrichment was analyzed by GSEA and KEGG while assessing in vivo tumor growth employing a xenograft model. JARID2 exhibited a significant overexpression in PCa tissues and cell lines, and was related to advanced N stage and escalated Gleason scores. Functionally, JARID2 enhanced cell proliferation and invasion in vitro, while its knockdown impeded tumor growth in vivo. Mechanistically, JARID2 interacted with and upregulated TET3, which activated FAK/PI3K/AKT signaling. TET3 knockdown attenuated the oncogenic effects of JARID2 overexpression, whereas TET3 overexpression restored the phenotypes induced by JARID2 silencing. Our findings identify JARID2 as a novel oncogenic factor in PCa that drives tumor progression associated with TET3-dependent FAK/PI3K/AKT signaling activation, highlighting a new epigenetic regulatory axis with potential diagnostic and therapeutic implications.