FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer

Abstract

Forkhead box M1 (FOXM1) is a member of the conserved forkhead box (FOX) transcription factor family. Over the last two decades, FOXM1 has emerged as a multifunctional oncoprotein and a robust biomarker of poor prognosis in many human malignancies. In this review article, we address the current knowledge regarding the mechanisms of regulation and oncogenic functions of FOXM1, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes in ovarian cancer, including: (1) cell proliferation, (2) invasion and metastasis, (3) chemotherapy resistance, (4) cancer stem cell (CSC) properties, (5) genomic instability, and (6) altered cellular metabolism. We additionally discuss the evidence for FOXM1 as a cancer biomarker, describe the rationale for FOXM1 as a cancer therapeutic target, and provide an overview of therapeutic strategies used to target FOXM1 for cancer treatment.

Keywords: FOXM1; forkhead box M1; high-grade serous ovarian cancer; oncogenes; oncoproteins; ovarian cancer; transcription factors.

Figure 1

Annual FOXM1 Publications. The data shown were generated from PubMed searches conducted on 04/13/21. The search terms used (all fields) were “FOXM1” (results in red), “FOXM1 cancer” (results in purple), and “FOXM1 ovarian cancer” (results in green). The first “FOXM1 ovarian cancer” PubMed record is the TCGA HGSC study published in 2011 [30].

Figure 2

FOXM1 isoforms and phosphorylation sites in ovarian cancer. Top: FOXM1 precursor mRNA (with introns and exons indicated) followed by FOXM1 mRNA structure (exons only). Exons shared by all FOXM1 isoforms are shown in green while alternative exons are shown in light purple. Bottom: Diagram of protein structure of the three major FOXM1 isoforms: (1) FOXM1a, which contains alternative exons Va and VIIa; (2) FOXM1b, which contains no alternative exons; and (3) FOXM1c, which contains alternative exon Va. The three major protein domains are indicated: N-terminal repressor domain (NRD, teal); DNA binding/forkhead domain (DBD/FHD, orange); and transactivation domain (TAD, red). The protein regions corresponding to the alternative exons Va and VIIa are shown in light purple. FOXM1 residues reported to be phosphorylated by three kinases important in ovarian cancer, CDK4/6 (dark blue), PLK1 (tan), and ERK1/2 (green), are indicated. Figure created with BioRender.com.

Figure 3

Mechanisms leading to FOXM1 overexpression and activation in ovarian cancer. Several mechanisms that are known to result in FOXM1 overexpression and/or activation in ovarian cancer are shown: (1) Chromosome 12p13.33, where the FOXM1 gene resides, experiences copy number gains and amplifications. (2) Upstream oncogenes (BET, GOF p53, E2F1, YAP, VprBPDCAF1, and ETV5) are overexpressed and upregulate FOXM1 transcription through chromatin modification and promoter activation. (3) Upstream tumor suppressors that regulate FOXM1 transcription (p53, Rb, and FOXO3A) experience inactivation through gene mutation or loss. (4) Post-transcriptional regulation by ncRNAs allow ribosomes to translate high levels of FOXM1 mRNA miR-370 and miR-149-5p, which typically destabilize FOXM1 mRNA, are sponged by lncPVT1, circPVT1, and hsa_circ_0061140. (5) Post-translation regulation stabilizes and activates FOXM1 protein. OTUB1 deubiquitinates FOXM1 and increases protein stability. PI3K/AKT, CDK4, CDK6, PLK1, and ERK1/2 phosphorylate FOXM1, which activates its transcription factor function. Figure created with BioRender.com.

Figure 4

The oncogenic functions of FOXM1 in ovarian cancer. FOXM1 transactivates genes by binding to gene enhancers and promoters, either directly through its DNA binding domain (DBD) or indirectly by interacting with other transcription factors (B-Myb, MuvB, and NFY). Through these two mechanisms, FOXM1 has been shown to promote several oncogenic phenotypes in ovarian cancer, including: (1) cellular proliferation, migration, and invasion; (2) DNA repair and chemotherapy resistance; (3) cancer cell stemness; (4) genomic instability and DNA replication stress; (5) altered cellular metabolism. Figure created with BioRender.com.