Forkhead Box M1 (FoxM1) Gene Is a New STAT3 Transcriptional Factor Target and Is Essential for Proliferation, Survival and DNA Repair of K562 Cell Line

Abstract

The forkhead box (Fox) M1 gene belongs to a superfamily of evolutionarily conserved transcriptional regulators that are involved in a wide range of biological processes, and its deregulation has been implicated in cancer survival, proliferation and chemotherapy resistance. However, the role of FoxM1, the signaling involved in its activation and its role in leukemia are poorly known. Here, we demonstrate by gene promoter analysis, Electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assays that FoxM1 is a new target of the STAT3 transcriptional activator. Additionally, FoxM1 is transcriptionally dependent on STAT3 signaling activation. Furthermore, we verified that FoxM1 is crucial for K562 cell proliferation, cell cycle checkpoints and viability and could be related to chemotherapeutic resistance. By microarray analysis, we determined the signaling pathways related to FoxM1 expression and its role in DNA repair using K562 cells. Our results revealed new signaling involved in FoxM1 expression and its role in leukemic cells that elucidate cellular mechanisms associated with the development of leukemia and disease progression.

Inhibition of FoxM1-Mediated DNA Repair by Imipramine Blue Suppresses Breast Cancer Growth and Metastasis

“…4F ). Consistent with this, FoxM1, which is known to regulate both G1/S and G2/M progression via several proteins, including cyclin D1, CDC25, AURAK, STMN1 and PLK1 (27), showed significantly reduced level in IB-treated breast cancer cells ( Figs. 4C and G ).…”

“…To begin to address the mechanism by which IB may regulate its targets, we focused on FoxM1 since several IB target genes including SKP2 (33), EXO1 (31), Rad51 (31), STMN1 (34) and AURKA (27) are reported to be transactivated by FoxM1. The dramatically reduced expression of FoxM1 in IB-treated breast cancer cells prompted us to test whether IB may directly interact with FoxM1.…”

“…There are two lines of evidences that further support the notion that interaction of IB with FoxM1 will result in FoxM1 transcriptional and translational instability. First, FoxM1 is reported to induce cyclin D1 transcription (27), while cyclin D1-CDK4 is reported to phosphorylate and stabilize FoxM1 protein (35). Therefore, it is likely that inhibition of FoxM1 by IB results in reduced cyclinD1-CDK4 levels ( Fig.…”

Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice

“…This was not due to alterations in the expression of the farnesoid X receptor (Fxr), a direct activator of the Foxm1 gene (figure 3F). However, levels of phosphorylated (activated) Stat3, a positive regulator of the Foxm1 gene,25 were much lower in Fgfr4 knockdown mice at 24 h after PH compared with controls, while the early Stat3 activation was not affected (figure 3G). This was not a consequence of interleukin (IL)-6 deficiency since serum levels of IL-6 and its upstream regulator tumour necrosis factor-α were even increased in mice with Fgfr4 knockdown at this time point (see online supplementary figure S4A,B).…”

Regulatory signatures of liver regeneration distilled by integrative analysis of mRNA, histone methylation, and proteomics

“…8E). A recent report has shown that Foxm1 is the target of the STAT3 transcriptional activator in K562 cells (27). We found that the amounts of STAT3 and its phosphorylated L H 3 K 2 7 m e 3 H 3 K 2 7 m e 3 H 3 1 R L R R H 3 K 2 7 m e 3 H 3 K 2 7 m e 3 3 K 2 7 m e 3 2 7 m 2 7 2 2 R L H 3 K 2 7 m e 3 1 R L H 3 K 2 7 m e 3 2 S h a m H 3 K 2 7 m e 3 1 S h a m H 3 K 2 7 m e 3 m e form were increased in the regenerating liver (Fig.…”