SMYD2 promotes oxidative stress-responsive lipid metabolism in melanoma by regulating H3K4 tri-methylation

Lipid metabolism is increasingly recognized as a critical role in cancer biology, influencing membrane dynamics, energy homeostasis, and cell survival. In melanoma, the specific regulatory mechanisms linking lipid metabolism and tumor progression remain poorly understood. Epigenetic modifiers have emerged as key regulators in metabolic reprogramming and tumor progression.

To investigate the role of SMYD2, a histone methyltransferase, in the regulation of lipid metabolism and oxidative stress in melanoma.

SMYD2 levels in melanoma tissues were analyzed in relation to patient prognosis. SMYD2 knockdown was achieved via shRNA in melanoma cell lines, followed by assays for proliferation, migration, and apoptosis. ChIP-qPCR was used to assess SMYD2-mediated trimethylation of H3K4 (H3K4me3) at the promoter regions of superoxide dismutase 1 (SOD1) and glutathione peroxidase 1 (GPX1). Fatty acid levels and markers of oxidative stress were measured using biochemical assays and western blot.

Elevated SMYD2 expression was correlated with poor prognosis in melanoma patients. SMYD2 knockdown significantly inhibited melanoma cell proliferation and migration while inducing apoptosis. Mechanistically, SMYD2 directly facilitated H3K4me3 at the promoters of SOD1 and GPX1, enhancing their transcription. The upregulation of SOD1 and GPX1 reduced oxidative stress levels and, in turn, promoted fatty acid synthesis and lipid accumulation.

SMYD2 functions as an oncogene in melanoma by epigenetically upregulating antioxidant genes SOD1 and GPX1, thereby alleviating oxidative stress and driving lipid reprogramming. These findings uncover a novel SMYD2-oxidative stress-lipid metabolism axis and highlight SMYD2 as a potential therapeutic target in melanoma.