Regulation of the master regulator FOXM1 in cancer

Abstract

FOXM1 (forkhead box protein M1) is a critical proliferation-associated transcription factor that is widely spatiotemporally expressed during the cell cycle. It is closely involved with the processes of cell proliferation, self-renewal, and tumorigenesis. In most human cancers, FOXM1 is overexpressed, and this indicates a poor prognosis for cancer patients. FOXM1 maintains cancer hallmarks by regulating the expression of target genes at the transcriptional level. Due to its potential role as molecular target in cancer therapy, FOXM1 was named the Molecule of the Year in 2010. However, the mechanism of FOXM1 dysregulation remains indistinct. A comprehensive understanding of FOXM1 regulation will provide novel insight for cancer and other diseases in which FOXM1 plays a major role. Here, we summarize the transcriptional regulation, post-transcriptional regulation and post-translational modifications of FOXM1, which will provide extremely important implications for novel strategies targeting FOXM1.

Keywords: FOXM1; Post-transcriptional; Post-translational; Regulation; Transcriptional.

Fig. 1

Genomic structure and coding isoforms in the FOXM1 gene and transcription factor binding sites in FOXM1 promoter region. a. Genomic structure and coding isoforms of the FOXM1 gene. b. Schematic diagram of transcription factor binding sites during FOXM1 promoter region. Green: activator, red: repressor, purple: cis-acting element could be bound by both activator and repressor

Fig. 2

FOXM1 expression profile from the TCGA database. The FOXM1 transcript per million are presented in differernt cancers and corresponding normal tissues, including ulterine corpus endometrial carcinoma (a), thyroid carcinoma (b), stomach adenocarcinoma (c), rectum adenocarcinoma (d), prostate adenocarcinoma (e), pheochromocytoma and paraganglioma (f), lung squamous cell carcinoma (g), lung adenocarcinoma (h), kidney renal clear cell carcinoma (i),kidney renal papillary cell carcinoma (j), kidney chromophobe (k),  head and neck squamous cell carcinoma (l), glioblastoma multiforme (m), esophageal carcinoma (n), colon carcinoma (o), cholangiocarcinoma (p), cervical squamous carcinoma (q), breast invasive carcinoma (r), liver hepatocellular carcinoma (s), bladder urothelial carcinoma (t)

Fig. 3

Kaplan–Meier analyses of overall survival according to FOXM1 expression levels in different cancer suffers, including adrenocortical carcinoma (a), glioma (b), colon adencarcinoma (c), kidney chromophobe (d),kidney renal clear cell carcinoma (e),kidney renal papillary cell carcinoma (f),liver hepatocellular carcinoma (g),lung adenocarcinoma (h),ulterine corpus endometrial carcinoma (m),uveal melanoma (n)

Fig. 4

Schematic diagram of FOXM1 regulation network. This schematic diagram attempts to address the regulation of FOXM1 in a spherical way. Green: promotion of FXOM1 expression or transcriptional activity; Red: repression of FOXM1 expression or transcriptional activity. ①.Transcriptional regulation of FOXM1: iTF (inhibitory transcription factor) binds to the promoter region of FOXM1 and inhibits its transcription. aTF (activating transcription factor) binds to the promoter region of FOXM1 and enhances its transcription. ②.Post-transcriptional regulation of FOXM1: m6A methylation of FOXM1 pre-mRNA and the miRNAs binding to 3′UTRs of FOXM1 mRNA and guiding FOXM1 are listed. lncRNAs can act as ceRNAs and block the suppression of FOXM1 by miRNAs. ③. Protein/RNA directly interacts with FOXM1 protein: The interaction of protein/RNA with FOXM1 protein alter the cellular localization, stabilization, or transcriptional activity of FOXM1. ④. Post-translational modifications of FOXM1 protein