The tumor suppressor p53 is a negative regulator of the carcinoma-associated transcription factor FOXQ1

Abstract

The forkhead box family transcription factor FOXQ1 is highly induced in several types of carcinomas, where it promotes epithelial-to-mesenchymal transition and tumor metastasis. The molecular mechanisms that lead to FOXQ1 deregulation in cancer are incompletely understood. Here, we used CRISPR-Cas9-based genomic locus proteomics and promoter reporter constructs to discover transcriptional regulators of FOXQ1 and identified the tumor suppressor p53 as a negative regulator of FOXQ1 expression. Chromatin immunoprecipitation followed by quantitative PCR as well as complementary gain and loss-of-function assays in model cell lines indicated that p53 binds close to the transcription start site of the FOXQ1 promoter, and that it suppresses FOXQ1 expression in various cell types. Consistently, pharmacological activation of p53 using nutlin-3 or doxorubicin reduced FOXQ1 mRNA and protein levels in cancer cell lines harboring wildtype p53. Finally, we observed that p53 mutations are associated with increased FOXQ1 expression in human cancers. Altogether, these results suggest that loss of p53 function-a hallmark feature of many types of cancer-derepresses FOXQ1, which in turn promotes tumor progression.

Keywords: FOXQ1; GloPro; colorectal cancer; forkhead box; gene regulation; gene transcription; p53; proteomics.