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Metastasis is the predominant reason for high mortality of hepatocellular carcinoma (HCC) patients. It is critical to explore the molecular mechanism underlying HCC metastasis. Here, we reported that transcription factor One Cut homeobox 2 (ONECUT2) functioned as an oncogene to facilitate HCC metastasis. Elevated ONECUT2 expression was positively correlated with increased tumor number, tumor encapsulation loss, microvascular invasion, poor tumor differentiation, and advanced TNM stage. Mechanistically, ONECUT2 directly bound to the promoters of fibroblast growth factor 2 (FGF2) and ATP citrate lyase (ACLY) and transcriptionally upregulated their expression. Knockdown of FGF2 and ACLY inhibited ONECUT2-mediated HCC metastasis, whereas upregulation of FGF2 and ACLY rescued ONECUT2 knockdown-induced suppression of HCC metastasis. ONECUT2 expression was positively correlated with FGF2 and ACLY expression in human HCC tissues. HCC patients with positive coexpression of ONECUT2/FGF2 or ONECUT2/ACLY exhibited the worst prognosis. In addition, FGF2 upregulated ONECUT2 expression through the FGFR1/ERK/ELK1 pathway, which formed an FGF2-FGFR1-ONECUT2 positive feedback loop. Knockdown of ONECUT2 inhibited FGF2-induced HCC metastasis. Furthermore, the combination of FGFR1 inhibitor PD173074 with ACLY inhibitor ETC-1002 markedly suppressed ONECUT2-mediated HCC metastasis. In summary, ONECUT2 was a potential prognostic biomarker in HCC and targeting this oncogenic signaling pathway may provide an efficient therapeutic strategy against HCC metastasis.

ONECUT2 facilitates hepatocellular carcinoma metastasis by transcriptionally upregulating FGF2 and ACLY