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Among epigenetic mechanisms, DNA methylation (methDNA) is gaining growing interest in cancer. Promoter hypomethylation is associated with oncogene activation while intragenic methDNA can be involved in transcriptional elongation, alternative spicing, and the activation of cryptic start sites. Several genes involved in the modulation of the tumor microenvironment are regulated by methDNA, including the\n                      <jats:italic>Solute Carrier Family 22 Member 1<\/jats:italic>\n                      7 (\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      ), which is involved in iron trafficking and extracellular matrix remodeling cooperating with the\n                      <jats:italic>Gelatinase-Associated Lipocalin<\/jats:italic>\n                      (\n                      <jats:italic>NGAL<\/jats:italic>\n                      ) ligand. However, the exact role of intragenic methDNA in cancer has not been fully investigated. Therefore, the aim of the present study is to explore the role of methDNA in the regulation of\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      in cutaneous melanoma (CM), used as a tumor model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Correlation and differential analyses between\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      expression and methDNA were performed using the data contained in The Cancer Genome Atlas and Gene Expression Omnibus databases. Functional studies on melanoma cell lines treated with 5-Azacytidine (5-Aza) were conducted to assess the correlation between methDNA and\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      expression. A validation study on the diagnostic potential of the in silico-identified\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      methDNA hotspot was finally performed by analyzing tissue samples obtained from CM patients and healthy controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The computational analyses revealed that\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      was significantly downregulated in CM, and its expression was related to promoter hypomethylation and intragenic hypermethylation. Moreover,\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      overexpression and hypermethylation of two intragenic methDNA hotspots were associated with a better clinical outcome in CM patients. The correlation between\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      methDNA and expression was confirmed in 5-Aza-treated cells. In agreement with in silico analyses, the\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      promoter methylation hotspot showed higher methDNA levels in CM samples compared to nevi. In addition, the methDNA levels of this hotspot were positively correlated with advanced CM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      methDNA hotspot could represent a promising biomarker for CM, highlighting the regulatory role of methDNA on\n                      <jats:italic>SLC22A17<\/jats:italic>\n                      expression. These results pave the way for the identification of novel epigenetic biomarkers and therapeutic targets for the management of CM patients.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-024-05622-9","type":"journal-article","created":{"date-parts":[[2024,10,2]],"date-time":"2024-10-02T04:02:17Z","timestamp":1727841737000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of SLC22A17 DNA methylation hotspot as a potential biomarker in cutaneous melanoma"],"prefix":"10.1186","volume":"22","author":[{"given":"Alessandro","family":"Lavoro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Falzone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Gattuso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe N.","family":"Conti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosario","family":"Caltabiano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Madonna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariaelena","family":"Capone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James A.","family":"McCubrey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo A.","family":"Ascierto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Libra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1255-6666","authenticated-orcid":false,"given":"Saverio","family":"Candido","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,2]]},"reference":[{"key":"5622_CR1","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1186\/1479-5876-8-56","volume":"8","author":"L Sigalotti","year":"2010","unstructured":"Sigalotti L, Covre A, Fratta E, Parisi G, Colizzi F, Rizzo A, et al. 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