UHRF1 silencing restrained the malignant phenotype of melanoma cells by inhibiting the HOXA9/HIF-1α axis-mediated glycolysis.

BACKGROUND: Ubiquitin-like with PHD and ring finger domains 1 (UHRF1) promotes DNA methylation of tumor suppressor genes, contributing to cancer development. Given its observed upregulation in melanoma, this study aimed to its functional roles and elucidate the underlying molecular mechanisms. METHODS: UHRF1 protein levels was evaluated in human melanoma tissues and cell lines. Gain- and loss-of-function experiments were conducted in two melanoma cell lines (A357 and SK-MEL-28), and cell proliferation, invasion, and apoptosis were examined. Homeobox A9 (HOXA9) promoter methylation was assessed using methylation-specific PCR. HOXA9-mediated transcriptional regulation of hypoxia-inducible factor 1α (HIF-1α) was validated in melanoma cells. Glycolysis was evaluated by detecting glucose uptake, lactate production, ATP levels, and extracellular acidification rate (ECAR). Additionally, a xenograft model was established using UHRF1-knockdown A375 cells, and tumor growth was monitored in nude mice. RESULTS: UHRF1 was significantly upregulated in melanoma tissues and cell lines. UHRF1 overexpression facilitated melanoma cell proliferation and invasion and inhibited apoptosis, while UHRF1 silencing led to an opposite result. Mechanistically, UHRF1 promoted DNMT1-mediated HOXA9 promoter methylation and inhibited HOXA9 expression in melanoma cells. HOXA9 transcriptionally inhibited HIF-1α expression in melanoma cells. Consequently, UHRF1 overexpression upregulated HIF-1α expression in melanoma cells, thus promoting glycolysis in melanoma cells. Moreover, HIF-1α overexpression neutralized the promoting effects of UHRF1 silencing on proliferation, invasion, and glycolysis. In addition, UHRF1 silencing suppressed melanoma growth in mice. CONCLUSION: UHRF1 silencing restrained the malignant phenotype of melanoma cells by inhibiting the HOXA9/HIF-1α axis-mediated glycolysis, thus suppressing tumor growth in mice.