{"doi":"10.1093/bjd/ljaf378","title":"Loss of ten-eleven translocation 2 (TET2) facilitates aggressive behaviour in cutaneous melanoma by inducing peroxisome proliferator-activated receptor-γ coactivator 1α expression and oxidative phosphorylation","abstract":"BACKGROUND: The induction of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α; encoded by PPARGC1A) expression and activation of oxidative phosphorylation (OXPHOS) is associated with disease progression and treatment resistance in patients with cutaneous melanoma. Loss of the TET2 (ten-eleven translocation 2)/5-hydroxymethylcytosine (5-hmC) epigenetic pathway is linked to melanoma aggressiveness, although the underlying mechanisms remain unclear. OBJECTIVES: To explore a relationship between TET2-mediated DNA hydroxymethylation and the induction of PPARGC1A/PGC-1α expression and activation of OXPHOS in melanoma. METHODS: RNA sequencing data from 368 melanoma metastases and 102 primary melanoma tumours were analysed, with tumours categorized as 'TET2-low' or 'TET2-high', based on TET2 gene expression. Differential gene expression and gene set enrichment analyses were done, with further validation using a tissue microarray comprised of 33 clinical specimens and a publicly available gene expression dataset from 209 primary tumours. Confirmatory in vitro and in vivo studies were performed using melanoma cell lines with altered TET2 and PGC-1α expression. 5-hmC and 5-methylcytosine levels at PPARGC1A were assessed using hydroxymethylated (hMeDIPseq) and methylated DNA immunoprecipitation sequencing. RESULTS: PGC-1α expression and activation of OXPHOS were significantly upregulated in TET2-low metastases and primary tumours. Tissue microarray analysis and gene expression studies showed an inverse relationship between TET2/5-hmC and PPARGC1A/PGC-1α expression and OXPHOS. In vitro and in vivo, PPARGC1A/PGC-1α expression and activation of OXPHOS was higher in TET2-low cells. hMeDIPseq identified significantly lower 5-hmC levels at an upstream PPARGC1A active enhancer in melanoma compared with naevi, in TET2-low compared with TET2-high cells and in cells expressing catalytically inactive TET2 compared with cells expressing wildtype TET2. Inhibition of PGC-1α expression and activation of OXPHOS mitigated migration and invasion in vitro and metastasis in vivo; TET2 loss was associated with resistance to mitogen-activated protein kinase (MAPK) pathway inhibition and enhanced sensitivity to OXPHOS inhibition. CONCLUSIONS: Loss of TET2 promotes activation of PGC-1α/OXPHOS in melanoma, driving metabolic reprogramming that supports tumour progression and resistance to MAPK inhibition in a subset of tumours. 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 a potential biomarker and a targetable pathway.","journal":"British Journal of Dermatology","year":2025,"id":554254,"datarank":0.16479184330021646,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.0,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9556,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1451514,"name":"Rui Fang","orcid":"0000-0002-3040-2903","position":1,"is_corresponding":false},{"id":754480,"name":"Shuyun Xu","orcid":"0000-0003-2762-4772","position":2,"is_corresponding":false},{"id":1212899,"name":"Anastasia Iris Karkempetzaki","orcid":null,"position":3,"is_corresponding":false},{"id":1206013,"name":"Laure Migayron","orcid":"0000-0003-2003-1923","position":4,"is_corresponding":false},{"id":1451515,"name":"Elizabeth Draper","orcid":"0009-0004-3185-8410","position":5,"is_corresponding":false},{"id":1426142,"name":"Justina Wang","orcid":null,"position":6,"is_corresponding":false},{"id":892921,"name":"Tobias Schatton","orcid":"0000-0003-1386-680X","position":7,"is_corresponding":false},{"id":653387,"name":"Anna Mandinova","orcid":"0000-0001-9273-0972","position":8,"is_corresponding":false},{"id":340206,"name":"George J. Murphy","orcid":"0000-0003-3464-793X","position":9,"is_corresponding":false},{"id":40506,"name":"Christine G. Lian","orcid":"0000-0003-4626-1612","position":10,"is_corresponding":false},{"id":236050,"name":"Grant M. Fischer","orcid":"0000-0003-3730-9004","position":0,"is_corresponding":true}],"reference_count":53,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:54:50.112989Z","pmid":"41016027","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}