cancers Review FOXM1: A Multifunctional Oncoprotein and Emerging Therapeutic Target in Ovarian Cancer Cassie Liu, Carter J. Barger and Adam R. Karpf * Eppley Institute and Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68918-6805, USA; [email protected] (C.L.); [email protected] (C.J.B.) * Correspondence: [email protected]; Tel.: +1-402-559-6115 Simple Summary: Ovarian cancer is a lethal disease in women with a 10-year survival rate of <40% worldwide. A key molecular alteration in ovarian cancer is the aberrant overexpression and activation of the transcription factor forkhead box M1 (FOXM1). FOXM1 regulates the expression of a multitude of genes that promote cancer, including those that increase the growth, survival, and metastatic spread of cancer cells. Importantly, FOXM1 overexpression is a robust biomarker for poor prognosis in pan-cancer and ovarian cancer. In this review, we first discuss the molecular mechanisms controlling FOXM1 expression and activity, with a specific emphasis on ovarian cancer. We then discuss the evidence for and the manner by which FOXM1 expression promotes aggressive cancer biology. Finally, we discuss the clinical utility of FOXM1, including its potential as a cancer biomarker and as a 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, Citation: Liu, C.; Barger, C.J.; Karpf, particularly in the context of ovarian cancer. FOXM1 and its associated oncogenic transcriptional A.R. FOXM1: A Multifunctional signature are enriched in >85% of ovarian cancer cases and FOXM1 expression and activity can Oncoprotein and Emerging be enhanced by a plethora of genomic, transcriptional, post-transcriptional, and post-translational Therapeutic Target in Ovarian Cancer. mechanisms. As a master transcriptional regulator, FOXM1 promotes critical oncogenic phenotypes Cancers 2021, 13, 3065. https:// doi.org/10.3390/cancers13123065 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 Academic Editor: Katsutoshi Oda 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 Received: 25 May 2021 used to target FOXM1 for cancer treatment. Accepted: 16 June 2021 Published: 19 June 2021 Keywords: FOXM1; forkhead box M1; transcription factors; oncogenes; oncoproteins; ovarian cancer; high-grade serous ovarian cancer Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. 1. Introduction 1.1. FOX Proteins and FOXM1 Discovery Forkhead box (FOX) proteins are a family of transcription factors defined by an evolutionarily conserved 80–100 amino acid domain called the forkhead box or winged- Copyright: © 2021 by the authors. helix motif [1–5]. There are 50 known FOX genes in the human genome divided into Licensee MDPI, Basel, Switzerland. 19 subfamilies (A–S) [6]. Sequence variation outside of the shared forkhead box motif This article is an open access article leads to diverse mechanisms of regulation and function between FOX subfamilies, and distributed under the terms and different FOX subfamilies are involved in critical cellular processes and govern organ conditions of the Creative Commons system functions [7]. For example, the FOXA subfamily participates in cellular metabolism Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ and the development of endoderm-derived organs [8]; the FOXC subfamily promotes 4.0/). blood vessel maturation and lymphatic sprouting [9]; the FOXO subfamily regulates Cancers 2021, 13, 3065. https://doi.org/10.3390/cancers13123065 https://www.mdpi.com/journal/cancers Cancers 2021, 13, 3065 2 of 40 Cancers 2021, 13, 3065 development of endoderm-derived organs [8]; the FOXC subfamily promotes blood ves- 2 of 39 sel maturation and lymphatic sprouting [9]; the FOXO subfamily regulates cell cycle arrest at G1, apoptosis, and resistance to oxidative and cellular stress [10]; the FOXP subfamily is involved cellin immune cycle arrest system at G1, functions, apoptosis, including and resistance coordinating to oxidative the development and cellular and stress [10]; the function of BFOXP and T subfamily lymphocytes is involved [11]. in immune system functions, including coordinating the FOXM1development is the sole member and function of the of FOXM B and subfamily T lymphocytes [6]. Historically, [11]. FOXM1 held alternative names:FOXM1 Trident is [12], the soleWIN member [13], hepatocyte of the FOXM nuclear subfamily factor 3 [6(HNF3)]. Historically, [14], fork FOXM1 held head homologalternative 11 (HFH-11) names: Trident[14,15], [12 FKHL16], WIN [13 [15],], hepatocyte M-phase nuclear phosphoprotein factor 3 (HNF3) 2 [14], fork (MPHOSPH2,head MPP2) homolog [16], 11MPM2-reactive (HFH-11) [14 ,phosphoprotein15], FKHL16 [15], 2 M-phase(MPP2) [16], phosphoprotein and TGT3 [17]. 2 (MPHOSPH2, In 1997, FOXM1MPP2) was [16 first], MPM2-reactive identified by Korver phosphoprotein et al. as Trident 2 (MPP2) from [16 mouse], and TGT3thymus [17 tissue]. In 1997, FOXM1 [12], by Yaowas et al. first as WIN identified from bya rat Korver insulinoma et al. ascell Trident line [13], from and mouse by Ye thymus et al. as tissue HNF- [12], by Yao 3/HFH-11 fromet al. a human as WIN colon from carcinoma a rat insulinoma cell line cell[14]. line These [13 initial], and studies by Ye etreported al. as HNF-3/HFH-11that FOXM1 is widelyfrom a expressed human colon in embryonic carcinoma tissues cell line but [14 ].that These its expression initial studies is restricted reported thatin FOXM1 is adult tissueswidely to actively expressed proliferating in embryonic cells, tissuessuch as but those that in its the expression thymus and is restricted gastrointesti- in adult tissues to nal tract [12–14,18].actively proliferatingIndeed, later cells, studies such confirmed as those in that the FOXM1 thymus andis highly gastrointestinal expressed tract in [12–14,18]. embryonic [19–22],Indeed, regenerative later studies [23–26], confirmed and that cancerous FOXM1 tissues is highly [27–29] expressed and all in of embryonic them [19–22], exhibit highregenerative proliferative [23 capacity.–26], and The cancerous FOXM1 tissues field [ 27and–29 publications] and all of them have exhibit increased high proliferative steadily sincecapacity. the year The 2000, FOXM1 with a field large and prop publicationsortion of studies have increasedfocused on steadily cancer since(Figure the year 2000, 1). with a large proportion of studies focused on cancer (Figure1). Figure 1. AnnualFigure FOXM1 1. Annual Publications. FOXM1 The Publications. data shown The were data generated shown fromwere PubMedgenerated searches from PubMed conducted searches on 04/13/21. The search terms usedconducted (all fields) on were04/13/21. “FOXM1” The search (results terms in red), used “FOXM1 (all fields) cancer” were (results “FOXM1” in purple), (results and in “FOXM1 red), “FOXM1 ovarian cancer” (results in green).cancer” The first(results “FOXM1 in purple), ovarian and cancer” “FOXM1 PubMed ovaria recordn cancer” is the (results TCGA HGSCin green). study The published first “FOXM1 in 2011 [30]. ovarian cancer” PubMed record is the TCGA HGSC study published in 2011 [30]. 1.2. FOXM1 1.2.Structure FOXM1 and Structure Transcriptional and Transcriptional Activity Activity The human FOXM1The human gene,FOXM1 locatedgene, at chromosome located at 12p13.33, chromosome consists 12p13.33, of ten consistsexons, in- of ten exons, cluding exonsincluding I–VIII and exons alternatively I–VIII and spliced alternatively exons Va spliced and VIIa exons [13,15,28]. Va and VIIaExon [ 13Va,15 en-,28]. Exon Va codes a 15 aminoencodes acid a 15insertion amino acidinto insertionthe DNA into binding the DNA domain binding (DBD), domain which (DBD), is a feature which is a feature not seen in othernot seen FOX in family other FOXmembers. family On members. the other On hand, the otherexon VIIa hand, encodes exon VIIa a 38 encodes amino a 38 amino acid insertionacid into insertion the transactivation into the transactivation domain (TAD) domain [13,14,28]. (TAD) Alternative [13,14,28 splicing]. Alternative of ex- splicing of ons Va and VIIaexons gives Va and rise VIIato three gives well-characterized rise to three well-characterized FOXM1 isoforms FOXM1 (Table isoforms 1): FOXM1a (Table1 ): FOXM1a includes all ten exons, FOXM1b omits alternative exons Va and VIIa, and FOXM1c includes includes all ten exons, FOXM1b omits alternative exons Va and VIIa, and FOXM1c in- alternative exon Va and omits alternative exon VIIa [13,14,28,29]. Notably, functional cludes alternative exon Va and omits alternative exon VIIa [13,14,28,29]. Notably, func- characterizations have shown that FOXM1b and FOXM1c are transcriptionally active while tional characterizations have shown that FOXM1b and FOXM1c are transcriptionally ac- FOXM1a is not [12,14,27,28,31,32]. Additional FOXM1 isoforms have also been reported in tive while FOXM1a is not