{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T19:46:45Z","timestamp":1785786405198,"version":"3.56.0"},"reference-count":55,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:00:00Z","timestamp":1758931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Stanley Robbins Memorial Research Fund of Brigham"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021671","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA247957"],"award-info":[{"award-number":["R01CA247957"]}],"id":[{"id":"10.13039\/501100021671","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100021671","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA258637"],"award-info":[{"award-number":["R01CA258637"]}],"id":[{"id":"10.13039\/501100021671","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,6]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The induction of peroxisome proliferator-activated receptor-\u03b3 coactivator 1\u03b1 (PGC-1\u03b1; 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>To explore a relationship between TET2-mediated DNA hydroxymethylation and the induction of PPARGC1A\/PGC-1\u03b1 expression and activation of OXPHOS in melanoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>RNA sequencing data from 368 melanoma metastases and 102 primary melanoma tumours were analysed, with tumours categorized as \u2018TET2-low\u2019 or \u2018TET2-high\u2019, 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-1\u03b1 expression. 5-hmC and 5-methylcytosine levels at PPARGC1A were assessed using hydroxymethylated (hMeDIPseq) and methylated DNA immunoprecipitation sequencing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>PGC-1\u03b1 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-1\u03b1 expression and OXPHOS. In vitro and in vivo, PPARGC1A\/PGC-1\u03b1 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-1\u03b1 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Loss of TET2 promotes activation of PGC-1\u03b1\/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\u2013metabolic axis as a critical determinant of melanoma aggressiveness and highlight TET2\/5-hmC as a potential biomarker and a targetable pathway.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/bjd\/ljaf378","type":"journal-article","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T12:08:08Z","timestamp":1758888488000},"page":"111-124","source":"Crossref","is-referenced-by-count":1,"title":["Loss of ten-eleven translocation 2 (TET2) facilitates aggressive behaviour in cutaneous melanoma by inducing peroxisome proliferator-activated receptor-\u03b3 coactivator 1\u03b1 expression and oxidative phosphorylation"],"prefix":"10.1093","volume":"194","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3730-9004","authenticated-orcid":false,"given":"Grant M","family":"Fischer","sequence":"first","affiliation":[{"name":"Department of Pathology, Brigham and Women\u2019s Hospital, Harvard Medical School , Boston, MA 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