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Inability to establish melanocyte\u2013keratinocyte contact and loss of the intercellular junction\u2019s integrity may contribute to melanoma development. Connexins, laminins and desmocollins have been implicated in the control of melanoma growth, where their reduced expression has been reported in metastatic lesions.<\/jats:p><jats:p>Objectives<\/jats:p><jats:p>The aim of this study was to investigate connexin 31\u00b71 (GJB5) expression and identify any association with BRAF mutational status, prognosis of patients with melanoma and mitogen-activated protein kinase (MAPK) inhibitor (MAPKi) treatment.<\/jats:p><jats:p>Methods<\/jats:p><jats:p>GJB5 expression was measured at RNA and protein level in melanoma clinical samples and established cell lines treated (or not) with BRAF and MEK inhibitors (MEKi), as well as in cell lines which developed MAPKi resistance. Findings were further validated and confirmed by analysis of independent datasets.<\/jats:p><jats:p>Results<\/jats:p><jats:p>Our analysis reveals significant downregulation of GJB5 expression in metastatic melanoma lesions compared with primary ones and in BRAF-mutated vs. BRAF-wildtype (BRAFWT) melanomas. Likewise, GJB5 expression is significantly lower in BRAFV600E compared with BRAFWT cell lines and increases on MAPKi treatment. MAPKi-resistant melanoma cells display a similar expression pattern compared with BRAFWT cells, with increased GJB5 expression associated with morphological changes. Enhancement of BRAFV600E expression in BRAFWT melanoma cells significantly upregulates miR-335-5p expression with consequent downregulation of GJB5, one of its targets. Furthermore, overexpression of miR-335-5p in two BRAFWT cell lines confirms specific GJB5 protein downregulation. Reverse transcriptase quantitative polymerase chain reaction analysis also revealed upregulation of miR-335 in BRAFV600E melanoma cells, which is significantly downregulated in cells resistant to MEKi. Our data were further validated using the TCGA_SKCM dataset, where BRAF mutations associate with increased miR-335 expression and inversely correlate with GJB5 expression. In clinical samples, GJB5 underexpression is also associated with patient overall worse survival, especially at early stages.<\/jats:p><jats:p>Conclusions<\/jats:p>","DOI":"10.1111\/bjd.20629","type":"journal-article","created":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T04:16:15Z","timestamp":1625804175000},"page":"117-128","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["GJB5 association with BRAF mutation and survival in cutaneous malignant melanoma"],"prefix":"10.1093","volume":"186","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1616-1151","authenticated-orcid":false,"given":"M.","family":"Scatolini","sequence":"first","affiliation":[{"name":"Molecular Oncology Laboratory Fondazione Edo ed Elvo Tempia 13875 Ponderano (BI) Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Patel","sequence":"additional","affiliation":[{"name":"Centre for Cell Biology and Cutaneous Research Blizard Institute Barts and The London School of Medicine and Dentistry Queen Mary University of London London E1 2AT UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"E.","family":"Grosso","sequence":"additional","affiliation":[{"name":"Molecular Oncology Laboratory Fondazione Edo ed Elvo Tempia 13875 Ponderano (BI) Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1041-7590","authenticated-orcid":false,"given":"M.","family":"Mello-Grand","sequence":"additional","affiliation":[{"name":"Cancer Genomics Laboratory Fondazione Edo ed Elvo Tempia 13900 Biella Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4000-2954","authenticated-orcid":false,"given":"P.","family":"Ostano","sequence":"additional","affiliation":[{"name":"Cancer Genomics Laboratory Fondazione Edo ed Elvo Tempia 13900 Biella Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Coppo","sequence":"additional","affiliation":[{"name":"Molecular Biotechnology Centre 10126 Torino Italy"},{"name":"Department of Clinical Bio-Resource Research and Development Graduate School of Medicine Kyoto University Kyoto Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Vitiello","sequence":"additional","affiliation":[{"name":"Oncogenomics Unit Core Research Laboratory Istituto Toscano Tumori Institute of Clinical Physiology CNR 56124 Pisa Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T.","family":"Venesio","sequence":"additional","affiliation":[{"name":"Pathology and Dermosurgery Units Candiolo Cancer Institute (FPO-IRCCS) 10060 Candiolo, Turin Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A.","family":"Zaccagna","sequence":"additional","affiliation":[{"name":"Pathology and Dermosurgery Units Candiolo Cancer 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