Loss of TET2 Facilitates Aggressive Behavior in Cutaneous Melanoma by Inducing PGC1α/Oxidative Phosphorylation (OXPHOS)

Abstract Background and Objectives Induction of PGC1α/oxidative phosphorylation (OXPHOS) is associated with disease progression and treatment resistance in cutaneous melanoma patients. Loss of the TET2/5-hydroxymethylcytosine (5-hmC) epigenetic pathway is linked to melanoma aggressiveness, although the underlying mechanisms remain unclear. Here we explored a relationship between TET2-mediated DNA hydroxymethylation and the induction of PGC1α/OXPHOS in melanoma. Methods RNA-sequencing data from 368 melanoma metastases (MMs) and 102 melanoma primaries (MPs) were analyzed, with tumors categorized as "TET2-low" and "TET2-high" based on gene expression. Differential gene expression and gene set enrichment analyses were conducted, with further validation using a tissue microarray (TMA) comprised of 33 clinical specimens and a publicly available gene expression dataset from 209 melanoma primaries. Confirmatory in vitro and in vivo studies were performed using melanoma cell lines with altered TET2 and PGC1α expression. 5-hmC and 5-mC levels at the PGC1α gene were assessed using hydroxymethylated and methylated DNA immunoprecipitation sequencing (hMeDIP-seq and MeDIP-seq). Results PGC1α/OXPHOS was significantly upregulated in TET2-low MMs and MPs. TMA analysis and gene expression studies showed an inverse relationship between TET2/5-hmC and PGC1α/OXPHOS expression. In vitro and in vivo, PGC1α/OXPHOS was higher in TET2-low cells. hMeDIP-seq identified significantly lower 5-hmC levels at an upstream PGC1α active enhancer in melanomas vs. nevi, in TET2-low vs. TET2-high cells, and in cells expressing catalytically inactive TET2 vs. cells expressing wild-type TET2. Inhibition of PGC1α/OXPHOS mitigated migration and invasion in vitro and metastasis in vivo, and TET2 loss associated with resistance to MAPK pathway inhibition and enhanced sensitivity to OXPHOS inhibition. Conclusion Loss of TET2 promotes activation of PGC1α/OXPHOS in melanoma, thereby driving metabolic reprogramming that supports tumor progression and resistance to MAPK inhibition in a subset of tumors. Importantly, this phenotype renders TET2-deficient melanomas selectively vulnerable to OXPHOS inhibition, identifying an actionable therapeutic opportunity. These findings establish an epigenetic–metabolic axis as a critical determinant of melanoma aggressiveness and highlight TET2/5-hmC as both a potential biomarker and a targetable pathway.