{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T17:03:06Z","timestamp":1772470986092,"version":"3.50.1"},"reference-count":51,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T00:00:00Z","timestamp":1772064000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Open Access Publishing Fund of the University of Vienna"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Many cancer-associated deaths result from metastases rather than primary tumors. Growing evidence suggests that DNA methylation alterations are crucial for inducing a plastic phenotype that allows cancer cells to adapt to the metastatic microenvironment. Brain metastases of melanoma (MBM) and glioblastoma (GB) share a neuroectodermal origin and the brain as tissue of residence, but their epigenetic regulation is poorly understood. Aiming at elucidating shared and tumor-distinct features, we analyzed the methylation of MGMT regulatory elements. We focused on MGMT because MGMT promoter methylation is used as a predictive marker for temozolomide response in GB, but its role in MBM has been discussed controversially. By targeting 12 CpG dinucleotides (CpGs) in the promoter, 68 CpGs in intergenic enhancers, and 31 CpGs in intragenic enhancers, we identified shared features, including an L-shaped relationship between promoter methylation and MGMT protein expression and an inverse L-shaped relationship between intragenic enhancer methylation and MGMT protein expression. GB exhibited higher methylation, particularly in promoter and intergenic enhancers, and stronger associations between methylation and overall survival than MBM. These results highlight both conserved and tumor-specific MGMT regulation, reflecting the complexity of epigenetic control in brain malignancies and emphasizing divergent evolution between MBM and GB.<\/jats:p>","DOI":"10.3390\/cells15050410","type":"journal-article","created":{"date-parts":[[2026,2,26]],"date-time":"2026-02-26T14:51:29Z","timestamp":1772117489000},"page":"410","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MGMT Promoter and Enhancer Methylation in Melanoma Brain Metastases and Glioblastoma: Shared and Distinct Features"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6187-6641","authenticated-orcid":false,"given":"Katharina","family":"P\u00fchringer","sequence":"first","affiliation":[{"name":"Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria"},{"name":"Vienna Doctoral School in Chemistry (DoSChem), University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benno","family":"Fehringer","sequence":"additional","affiliation":[{"name":"Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2002-9727","authenticated-orcid":false,"given":"Katja","family":"Zappe","sequence":"additional","affiliation":[{"name":"Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0014-1658","authenticated-orcid":false,"given":"Walter","family":"Berger","sequence":"additional","affiliation":[{"name":"Center for Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6750-2599","authenticated-orcid":false,"given":"Serge","family":"Weis","sequence":"additional","affiliation":[{"name":"Division of Neuropathology, Department of Pathology and Molecular Pathology, Kepler University Hospital GmbH, Johannes Kepler University, 4040 Linz, Austria"},{"name":"Clinical Research Institute for Neurosciences, Johannes Kepler University, 4020 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Spiegl-Kreinecker","sequence":"additional","affiliation":[{"name":"Clinical Research Institute for Neurosciences, Johannes Kepler University, 4020 Linz, Austria"},{"name":"Department of Neurosurgery, Kepler University Hospital GmbH, Johannes Kepler University, 4040 Linz, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8699-674X","authenticated-orcid":false,"given":"Margit","family":"Cichna-Markl","sequence":"additional","affiliation":[{"name":"Institute of Analytical Chemistry, Faculty of Chemistry, University of Vienna, 1090 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1016\/j.cell.2023.03.003","article-title":"Metastasis","volume":"186","author":"Gerstberger","year":"2023","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"670","DOI":"10.1016\/j.cell.2016.11.037","article-title":"Emerging Biological Principles of Metastasis","volume":"168","author":"Lambert","year":"2017","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1038\/s41572-018-0055-y","article-title":"Brain metastases","volume":"5","author":"Achrol","year":"2019","journal-title":"Nat. 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