HOXB8 promotes invasion and metastasis of high-grade serous ovarian cancer via suppression of the KDM6B/C/EBPα signaling axis.

BACKGROUND: High-grade serous ovarian cancer (HGSOC) constitutes the deadliest form of gynecologic tumor, with its high invasiveness and peritoneal dissemination closely associated with epigenetic regulation. HOXB8 has been implicated in tumor-promoting functions, but its role in regulating the KDM6B/C/EBPα signaling axis in HGSOC metastasis has not been fully elucidated. Here, we examined how HOXB8 regulates this pathway and downstream CCND1 expression, as well as its impact on ovarian cancer cell invasion and migration. METHODS: SKOV3 human ovarian cancer cells were subjected to HOXB8 knockdown or overexpression via small interfering RNA (siRNA) transfection and plasmid-mediated gene delivery. Functional rescue assays were performed with KDM6B-specific siRNA and the H3K27me3 methyltransferase inhibitor GSK126. The expression of KDM6B, C/EBPα, CCND1, and overall H3K27me3 was examined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Levels of inflammatory cytokines were determined using enzyme-linked immunosorbent assay (ELISA), while cellular growth, motility, and invasive ability were evaluated through Cell Counting Kit-8 (CCK-8), Transwell, and wound-healing assays. RESULTS: HOXB8 overexpression significantly downregulated KDM6B and C/EBPα expression, upregulated CCND1 and H3K27me3 levels, increased tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and C-reactive protein (CRP) secretion, and markedly enhanced cellular growth, motility, and invasive ability. HOXB8 knockdown produced the opposite effects. KDM6B silencing phenocopied the pro-invasive effects of HOXB8 overexpression. In contrast, administration of GSK126 partly counteracted the reduction of C/EBPα and the increase of CCND1 triggered by KDM6B depletion, while also attenuating cytokine secretion and invasive capacity. CONCLUSIONS: HOXB8 promotes inflammatory responses and metastatic potential in HGSOC cells by suppressing the KDM6B/C/EBPα signaling axis, inducing aberrant H3K27me3 modification, and upregulating CCND1. Targeting HOXB8-mediated pathways may provide novel therapeutic opportunities for limiting ovarian cancer progression.