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Additionally, EZH2 overexpression leads to epigenetic silencing of tumor suppressor and cell differentiation genes. Here, we investigate the mechanism of EZH2 transcriptional activation in ATC. We used several luciferase reporter constructs with deletion of transcription factor (TF) binding sites identified in silico to determine EZH2 minimal promoter in ATC. MAPK signaling blockage with U0126, TF overexpression and knock-down strategies were used to evaluate EZH2 expression and reporter plasmid response, and the cross talk with TFs. As a result, we observed that EZH2 transcription is regulated by a minimal promoter of 107 bp (E3\/4 region), that contains binding sites for TF NFYA, YY1 and FOXM1, highly expressed in ATC, that when deleted reduced EZH2 promoter activation. MAPK blockage reduced EZH2 and influenced YY1 and FOXM1 TF levels, while overexpression of NFYA, YY1 and FOXM1 resulted in pro-tumoral effects and EZH2 upregulation in papillary thyroid cancer cells. On the other hand, FOXM1 knock-down reduced EZH2 activation in ATC cells. Thus, we identified the minimal promoter region essential for EZH2 activation in ATC that is controlled by MAPK signaling in crosstalk with TFs.<\/jats:p>","DOI":"10.3390\/ijms27146402","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T09:32:54Z","timestamp":1784539974000},"page":"6402","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activation of EZH2 Promoter Is Mediated by MAPK Signaling Regulated Transcription Factors in Anaplastic Thyroid Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9110-5788","authenticated-orcid":false,"given":"Marcella Maringolo","family":"Cristov\u00e3o","sequence":"first","affiliation":[{"name":"Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6405-0635","authenticated-orcid":false,"given":"Diego Claro","family":"de Mello","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8403-4459","authenticated-orcid":false,"given":"Edna Teruko","family":"Kimura","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-000, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0567-5432","authenticated-orcid":false,"given":"Cesar Seigi","family":"Fuziwara","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of S\u00e3o Paulo (USP), S\u00e3o Paulo 05508-000, SP, Brazil"},{"name":"Department of Biochemistry, Escola Paulista de Medicina, Universidade Federal de S\u00e3o Paulo (UNIFESP), S\u00e3o Paulo 04044-020, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","first-page":"394","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. 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