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Overactive <jats:italic>MYC<\/jats:italic> may cause miRNAs\u2019 expression deregulation through transcriptional and post-transcriptional mechanisms and epigenetic alterations are also involved in miRNAs dysregulation. Herein, we aimed to elucidate the role of regulatory network between <jats:italic>MYC<\/jats:italic> and miRNAs in prostate carcinogenesis. <jats:italic>MYC<\/jats:italic> expression was found upregulated in PCa cases and matched precursor lesions. MicroRNA\u2019s microarray analysis of PCa samples with opposed <jats:italic>MYC<\/jats:italic> levels identified miRNAs significantly overexpressed in high-<jats:italic>MYC<\/jats:italic> PCa. However, validation of miR-27a-5p in primary prostate tissues disclosed downregulation in PCa, instead, correlating with aberrant promoter methylation. In a series of castration-resistant PCa (CRPC) cases, miR-27a-5p was upregulated, along with promoter hypomethylation. <jats:italic>MYC<\/jats:italic> and miR-27a-5p expression levels in LNCaP and PC3 cells mirrored those observed in hormone-na\u00edve PCa and CRPC, respectively. ChIP analysis showed that miR-27a-5p expression is only regulated by c-Myc in the absence of aberrant promoter methylation. MiR-27a-5p knockdown in PC3 cells promoted cell growth, whereas miRNA forced expression in LNCaP and stable <jats:italic>MYC<\/jats:italic>-knockdown PC3 cells attenuated the malignant phenotype, suggesting a tumor suppressive role for miR-27a-5p. Furthermore, miR-27a-5p upregulation decreased EGFR\/Akt1\/mTOR signaling. We concluded that miR-27a-5p is positively regulated by <jats:italic>MYC<\/jats:italic>, and its silencing due to aberrant promoter methylation occurs early in prostate carcinogenesis, concomitantly with loss of <jats:italic>MYC<\/jats:italic> regulatory activity. Our results further suggest that along PCa progression, miR-27a-5p promoter becomes hypomethylated, allowing for <jats:italic>MYC<\/jats:italic> to resume its regulatory activity. However, the altered cellular context averts miR-27a-5p from successfully accomplishing its tumor suppressive function at this stage of disease.<\/jats:p>","DOI":"10.1038\/s41419-017-0241-y","type":"journal-article","created":{"date-parts":[[2018,2,7]],"date-time":"2018-02-07T14:19:49Z","timestamp":1518013189000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["MicroRNA-27a-5p regulation by promoter methylation and MYC signaling in prostate carcinogenesis"],"prefix":"10.1038","volume":"9","author":[{"given":"Daniela","family":"Barros-Silva","sequence":"first","affiliation":[]},{"given":"Pedro","family":"Costa-Pinheiro","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8641-8368","authenticated-orcid":false,"given":"Henrique","family":"Duarte","sequence":"additional","affiliation":[]},{"given":"Elsa Joana","family":"Sousa","sequence":"additional","affiliation":[]},{"given":"Adriane Feij\u00f3","family":"Evangelista","sequence":"additional","affiliation":[]},{"given":"In\u00eas","family":"Gra\u00e7a","sequence":"additional","affiliation":[]},{"given":"Isa","family":"Carneiro","sequence":"additional","affiliation":[]},{"given":"Ana Teresa","family":"Martins","sequence":"additional","affiliation":[]},{"given":"Jorge","family":"Oliveira","sequence":"additional","affiliation":[]},{"given":"Andr\u00e9 L.","family":"Carvalho","sequence":"additional","affiliation":[]},{"given":"M\u00e1rcia M.","family":"Marques","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3171-4666","authenticated-orcid":false,"given":"Rui","family":"Henrique","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4186-5345","authenticated-orcid":false,"given":"Carmen","family":"Jer\u00f3nimo","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2018,2,7]]},"reference":[{"key":"241_CR1","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1001\/jamaoncol.2015.0735","volume":"1","author":"C Fitzmaurice","year":"2015","unstructured":"Fitzmaurice, C. et al. 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