Predicting FOXM1-Mediated Gene Regulation through the Analysis of Genome-Wide FOXM1 Binding Sites in MCF-7, K562, SK-N-SH, GM12878 and ECC-1 Cell Lines

Keunsoo Kang,Hoo Hyun Kim,Yoonjung Choi,Sungryul Yu,Kyung Hyun Yoo

doi:10.3390/ijms21176141

Abstract

Forkhead box protein M1 (FOXM1) is a key transcription factor (TF) that regulates a common set of genes related to the cell cycle in various cell types. However, the mechanism by which FOXM1 controls the common gene set in different cellular contexts is unclear. In this study, a comprehensive meta-analysis of genome-wide FOXM1 binding sites in ECC-1, GM12878, K562, MCF-7, and SK-N-SH cell lines was conducted to predict FOXM1-driven gene regulation. Consistent with previous studies, different TF binding motifs were identified at FOXM1 binding sites, while the NFY binding motif was found at 81% of common FOXM1 binding sites in promoters of cell cycle-related genes. The results indicated that FOXM1 might control the gene set through interaction with the NFY proteins, while cell type-specific genes were predicted to be regulated by enhancers with FOXM1 and cell type-specific TFs. We also found that the high expression level of FOXM1 was significantly associated with poor prognosis in nine types of cancer. Overall, these results suggest that FOXM1 is predicted to function as a master regulator of the cell cycle through the interaction of NFY-family proteins, and therefore the inhibition of FOXM1 could be an attractive strategy for cancer therapy.

Highlights

The forkhead (FKH) box protein M1 (FOXM1) belongs to the forkhead transcription factor family, which plays a key role in cell cycle progression, including the G1/S phase transition and progression into mitosis [1,2]
To understand the molecular mechanism underlying this characteristic, we reanalyzed Forkhead box protein M1 (FOXM1) ChIP-seq data sets performed in ECC-1, GM12878, K562, MCF-7, and SK-N-SH cell lines from the encyclopedia of DNA elements (ENCODE) website [21]
We performed a series of motif analyses to characterize whether motifs identified in FOXM1 binding sites varied among cell lines

Summary

Introduction

The forkhead (FKH) box protein M1 (FOXM1) belongs to the forkhead transcription factor family, which plays a key role in cell cycle progression, including the G1/S phase transition and progression into mitosis [1,2]. Emerging evidence suggests that aberrant activation of FOXM1 signaling stimulates tumorigenesis and tumor aggressiveness in various cancer cells by increasing drug resistance and migration/invasion [3,4]. The remaining patients acquire resistance to this type of therapy, which is known to be mediated by a positive feedback regulatory loop between FOXM1 and ERα [11]. Inhibition of FOXM1 activity using RNA interference system and chemical compounds displayed reduced tumor growth and invasiveness, as well as increased chemosensitivity [12,13,14]. These results underline that FOXM1 is a promising target for anticancer therapy

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Results