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In HeLa cells, although VPA leads to decreased DNA 5-methylcytosine (5mC) levels, the demethylation pathway involved in this effect is not fully understood. We investigated this process using flow cytometry, ELISA, immunocytochemistry, Western blotting and RT-qPCR in G1 phase-arrested and proliferative HeLa cells compared to the presumably passive demethylation promoted by 5-aza-CdR. The results revealed that VPA acts predominantly on active DNA demethylation because it induced TET2 gene and protein overexpression, decreased 5mC abundance, and increased 5-hydroxy-methylcytosine (5hmC) abundance, in both G1-arrested and proliferative cells. However, because VPA caused decreased <jats:italic>DNMT1<\/jats:italic> gene expression levels, it may also act on the passive demethylation pathway. 5-aza-CdR attenuated <jats:italic>DNMT1<\/jats:italic> gene expression levels but increased TET2 and 5hmC abundance in replicating cells, although it did not affect the gene expression of <jats:italic>TETs<\/jats:italic> at any stage of the cell cycle. Therefore, 5-aza-CdR may also function in the active pathway. Because VPA reduces DNA methylation levels in non-replicating HeLa cells, it could be tested as a candidate for the therapeutic reversal of DNA methylation in cells in which cell division is arrested.<\/jats:p>","DOI":"10.1038\/s41598-019-54848-x","type":"journal-article","created":{"date-parts":[[2019,12,3]],"date-time":"2019-12-03T11:04:18Z","timestamp":1575371058000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Sodium valproate and 5-aza-2\u2032-deoxycytidine differentially modulate DNA demethylation in G1 phase-arrested and proliferative HeLa cells"],"prefix":"10.1038","volume":"9","author":[{"given":"Marina Amorim","family":"Rocha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovana Maria Breda","family":"Veronezi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina Barreto","family":"Felisbino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Silvia Viccari","family":"Gatti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wirla M. 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