biostudies-literatureMitchell AVNCI NIH HHSNIH HHS6548https://www.ebi.ac.uk/biostudies/studies/S-EPMC9626503biostudies-literatureUnknown13(1)Aberrant expression of the Forkhead box transcription factor, FOXQ1, is a prevalent mechanism of epithelial-mesenchymal transition (EMT) and metastasis in multiple carcinoma types. However, it remains unknown how FOXQ1 regulates gene expression. Here, we report that FOXQ1 initiates EMT by recruiting the MLL/KMT2 histone methyltransferase complex as a transcriptional coactivator. We first establish that FOXQ1 promoter recognition precedes MLL complex assembly and histone-3 lysine-4 trimethylation within the promoter regions of critical genes in the EMT program. Mechanistically, we identify that the Forkhead box in FOXQ1 functions as a transactivation domain directly binding the MLL core complex subunit RbBP5 without interrupting FOXQ1 DNA binding activity. Moreover, genetic disruption of thNature communicationsFOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis.PMC9626503S10 OD010700F31 CA236245R21 CA256423P30 CA022453Wu LWang CMatherly LMitchell AVJames Block CZhang MZhang SWu GZhao YDou YYang ZKidder BZhang XHackett JChen WCraig DBDang YPile LAZhang BGibson HfalseFOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis.Aberrant expression of the Forkhead box transcription factor, FOXQ1, is a prevalent mechanism of epithelial-mesenchymal transition (EMT) and metastasis in multiple carcinoma types. However, it remains unknown how FOXQ1 regulates gene expression. Here, we report that FOXQ1 initiates EMT by recruiting the MLL/KMT2 histone methyltransferase complex as a transcriptional coactivator. We first establish that FOXQ1 promoter recognition precedes MLL complex assembly and histone-3 lysine-4 trimethylation within the promoter regions of critical genes in the EMT program. Mechanistically, we identify that the Forkhead box in FOXQ1 functions as a transactivation domain directly binding the MLL core complex subunit RbBP5 without interrupting FOXQ1 DNA binding activity. Moreover, genetic disruption of th2022-01-01T00:00:00Z2022 Nov2025-04-21T17:13:26.373Z2025-02-19T00:31:51.343ZS-EPMC96265033631964310.1038/s41467-022-34239-z