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

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.

Nuclear isoform of RAPH1 interacts with FOXQ1 to promote progression and radioresistance in triple-negative breast cancer through the STAT3 pathway

“…Our data show that FOXQ1 is signi cantly upregulated in radioresistant TNBC cells, suggesting its involvement in TNBC radioresistance. Previous studies have reported that FOXQ1 can activate EMT and promote metastasis and chemoresistance in breast cancer [18,33]. Consistently, our results indicate that FOXQ1 plays a pivotal role in the maintenance of radioresistance in TNBC cells.…”

“…However, overexpression of FOXQ1 alone is not su cient to induce the radioresistance in TNBC cells. Mitchell et al [33] demonstrated that FOXQ1 recruits the MLL/KMT2 histone methyltransferase complex to regulate gene expression. Meng et al [18] reported that FOXQ1 can interact with TWIST1 to modulate downstream target genes.…”

Molecular characterization of FOX factors and Wnt signalling interplay in human cancers

“…Similarly, FOXQ1 has been described as oncogene in several human cancers [45,[52][53][54], and will be discussed in more detail in this thesis (see section 1.2.3).…”

“…FOXQ1 has been primarily associated with the direct transcriptional regulation of target genes that drive EMT, such the downregulation of epithelial CDH1 expression and the upregulation of the CDH2 mesenchymal marker [40,72]. Additionally, other mechanisms such as the regulation of other EMT-associated transcription factors [53,73,74] or the induction of changes in the chromatin status have been described [52].…”

FOXQ1 promotes pancreatic cancer cell proliferation, tumor stemness, invasion and metastasis through regulation of LDHA-mediated aerobic glycolysis

“…The transcription factor forkhead box Q1 (FOXQ1), a member of the FOX family(8), contributes to a variety of physiological processes, including cellular senescence (9), glucose metabolism (10), lactate synthesis (11), and cardiac brosis (12). FOXQ1 also acts as a signi cant role in the biological processes that contribute to malignancy, including invasion, apoptosis, and epithelial-mesenchymal transition (13), in diverse cancers, including breast cancer, rectal cancer, and intrahepatic cholangiocarcinoma (14)(15)(16)(17)(18). Nevertheless, the role of FOXQ1 in PC have not been clari ed.…”