FOXQ1 recruits the MLL complex to activate transcription of EMT and promote breast cancer metastasis

Allison V. Mitchell, Ling Wu, C. James Block, Mu Zhang, Justin Hackett, Douglas B. Craig, Wei Chen, Yongzhong Zhao, Bin Zhang, Yongjun Dang, Xiaohong Zhang, Shengping Zhang, Chuangui Wang, Heather Gibson, Lori A. Pile, Benjamin Kidder, Larry Matherly, Zhe Yang, Yali Dou and Guojun Wu ()
Additional contact information
Allison V. Mitchell: Wayne State University School of Medicine
Ling Wu: Wayne State University School of Medicine
C. James Block: Wayne State University School of Medicine
Mu Zhang: Wayne State University School of Medicine
Justin Hackett: Wayne State University School of Medicine
Douglas B. Craig: Wayne State University School of Medicine
Wei Chen: Wayne State University School of Medicine
Yongzhong Zhao: Icahn Mount Sinai School of Medicine
Bin Zhang: Icahn Mount Sinai School of Medicine
Yongjun Dang: Fudan University
Xiaohong Zhang: Wayne State University School of Medicine
Shengping Zhang: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Chuangui Wang: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
Heather Gibson: Wayne State University School of Medicine
Lori A. Pile: Wayne State University
Benjamin Kidder: Wayne State University School of Medicine
Larry Matherly: Wayne State University School of Medicine
Zhe Yang: Wayne State University School of Medicine
Yali Dou: University of Michigan Medical School
Guojun Wu: Wayne State University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-22

Abstract: Abstract 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 the FOXQ1-RbBP5 interaction or pharmacologic targeting of KMT2/MLL recruitment inhibits FOXQ1-dependent gene expression, EMT, and in vivo tumor progression. Our study suggests that targeting the FOXQ1-MLL epigenetic axis could be a promising strategy to combat triple-negative breast cancer metastatic progression.

Date: 2022
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DOI: 10.1038/s41467-022-34239-z

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