FOXM1 is an oncogenic transcription factor that promotes tumor growth, metastasis, and progression of drug resistance, and its high expression correlates with poor patient survival across various solid tumors. Mutations in the p53 tumor suppressor, a common genetic alteration in approximately half of the human tumors, lead to FOXM1 overexpression. Emerging evidence indicates that a small subpopulation of cancer cells, cancer stem cells (CSCs), within tumors contributes to relapse, metastasis, and progression due to their roles in tumor initiation, self-renewal, differentiation, and therapy resistance. The clinical significance of CSCs on patient prognosis underscores the need for CSC-targeted therapies. FOXM1 plays a significant role in CSC-proliferation and survival, interacting with key stemness-related and pluripotency-associated transcription factors such as SOX2, OCT4, NANOG, and stem cell markers CD133, CD44, CD24, and ALDH. Notably, in-vivo genetic targeting of FOXM1 has been shown to block tumor growth in experimental models. However, there is currently no FDAapproved therapy specifically targeting FOXM1. Given its pivotal role, developing FOXM1-targeted therapies holds significant potential to overcome therapy resistance, halt cancer progression, and improve patient survival. This review evaluates the latest data on the role of FOXM1 in CSCs and explores potential strategies for targeting FOXM1 as a therapeutic approach.

• FOXM1

• Cancer stem cells

• Drug resistance

• FOXM1 inhibitors

• Stemness

Biltekin E, Ozpolat B (2024) FOXM1: A Promising Target for Cancer Stemness. J Cancer Biol Res 11(2): 1146.

ABC Transporter: ATP Binding Cassette Transporter; AFP: Alfa-fetoprotein; BC: Breast Cancer; CC: Cervical Cancer; CSCs: Cancer Stem Cells; EMT: Epithelial-Mesenchymal Transition; FOX: Forkhead-box; GBM: Glioblastoma; HCC: Hepatocellular Carcinoma; LCSCs: Liver Cancer Stem Cells; NPC: Nasopharyngeal Cancer; OCSCs: Ovarian Cancer Stem Cells; TNBC: Triple Negative Breast Cancer; Ref.: References.

In 2024, over 2 million new cancer cases are expected in the United States alone, while globally, cancer remains the second leading cause of death [1,2]. Despite significant advancements in cancer treatments, such as immunotherapy, targeted therapies, and nanomedicine, resistance to these new treatments, as well as conventional therapies like chemotherapy and radiotherapy, remains a critical challenge. This resistance contributes to relapses and poor patient survival [3-5].

Oncogenic transition from healthy cells is driven by various intrinsic and extrinsic factors. Extrinsic factors such as inflammation, viral infections, chemical exposure, radiation, unhealthy dietary habits, and ageing can facilitate oncogenesis. These factors lead to genetic mutations and epigenetic alterations, which are considered intrinsic mediators, alongside heredity factors [6,7].

Cancer stem cells (CSCs), a small but distinct population within tumors, play a crucial role in tumor initiation, metastasis, and relapses. CSCs are characterized by their ability to self-renew, differentiate, proliferate, produce progenitor cells, and resist treatments [4,8-12]. The concept of CSCs was first established in acute myeloid leukemia with CD34+/CD38- leukemia initiating cells. Subsequent research on solid tumors demonstrated that CD44+/CD24-/Lin- cells could form tumors in severe immune- deficient mice with breast cancer [11-13].

To identify CSCs and understand intratumoral heterogeneity, various cell surface markers such as CD44, CD24, C133, CD34, CD38, CD133, CD117, CD271, CXCR4, Lgr5, EPCAM, and ALDH enzyme activity have been widely used [10,14-20]. For instance, Leng et al. showed that LGR5+/CD44+/EPCAM+ cells had a higher tumor-initiating capacity and could form spheroids, unlike CD44-/EPCAM- cells, with Lgr5 positivity playing a major role [10]. Similarly, Fumagalli et al. highlighted the metastatic abilities and plasticity of CSCs, showing that LGR5- cells could migrate and extravasate into blood circulation, but expressed LGR5 upon liver inoculation, whereby ablation of LGR5 expression inhibits the liver metastasis of inoculated LGR5– cells [9]. In glioblastoma model, treatment with the chemotherapeutic agent Temozolamide increased the number of CSCs by converting non-CSCs to CSCs [21]. The dormancy, high expression of pluripotency-related transcription factors, and high drug efflux capacity of CSCs contribute to their drug resistance [22,23].

FOXM1 is a transcription factor belonging to the forkhead-box (FOX) protein family, which comprises 19 different subclasses characterized by a “winged-helix” structure [24,25]. FOX proteins play essential roles in development, cell differentiation, cellular hemostasis, apoptosis, and tumorigenesis [25-28]. FOXM1, which has four subtypes (FOXM1a, FOXM1b, FOXM1c, FOXM1d), is involved in embryogenesis, neuronal stem cell proliferation, lung vasculogenesis, and hepatoblastoma proliferation [29-32]. Dysregulation of FOXM1 has been observed in various cancers and is linked to cancer cell proliferation, survival, epithelial- mesenchymal transition (EMT), invasion, migration, poor patient survival, treatment resistance, and cancer stemness [33-35]. FOXM1 is suppressed by the tumor suppressor transcription factor p53, and mutations in p53, present in a half of human tumors, lead to overexpression of FOXM1 [36,37] [Figure 1].

Figure 1: FOXM1, A Promising Target for Cancer Stemness

FOXM1 is overexpressed in a broad range of tumors, and its upregulation is associated with advanced tumor stages. A meta- analysis by Li et al. revealed that more than half of the patients with solid tumors exhibited higher FOXM1 protein expression, correlating with poor overall survival [38]. Analysis of the TCGA database showed that 22 out of 31 different tumor types have FOXM1 overexpression; in addition, patients with metastatic tumors express significantly higher levels of FOXM1 compared with early-stage cancer [39]. Our recent Kaplan Meier Plotter Survival Analysis showed that higher FOXM1 mRNA expression is significantly correlated with poor patient survival in breast, lung, pancreatic, ovarian, and metastatic gastric cancers [Figure 2].

Figure 2: Kaplan Meier Survival Analysis of FOXM1 mRNA Expression on Overall Survival of Breast Cancer, Lung Cancer, Pancreatic Cancer, Ovarian Cancer, Colon and Gastric Cancer Patients show that FOXM1 expression is associated with shorter overall survival (OS) in the majority of most commonly diagnosed cancers. In gastric cancer, significant association between FOXM1 expression and poor survival is detected in the patients with an advance stage (stage IV)

SOX2, a transcription factor and pluripotency marker involved in embryogenesis, has been linked to stemness, cell proliferation, plasticity, and therapy resistance in numerous tumors, including esophageal squamous cancer, gastric cancer, ovarian cancer, medulloblastoma, glioblastoma, lung, and breast cancer [33,40- 47]. Genomic analysis in glioblastoma patients showed that FOXM1 directly binds to the promotor of SOX2, driving its expression. FOXM1 knockdown suppresses SOX2 expression and sensitizes glioblastoma cells to radiation [48]. Studies in in vitro and in vivo tumor models of Triple Negative Breast Cancer (TNBC) demonstrated that FOXM1 plays a role in the regulation of SOX2 via DNMT1/FOXO3a/FOXM1/SOX2 signaling axis and its inhibition suppresses CD44+/CD24- and ALDH+ stem cell population significantly [49]. FOXM1 has also been reported as a regulator of SOX2 in colorectal cancer by inhibiting the promoter activity of SOX2 [50]. Recently, another study revealed the link between the modulatory effect of the FOXM1 on SOX2 axis in colorectal cancer as the inhibition of FOXM1/SOX2 signaling reduced CXCR4, stemness marker expression and spheroid formation [51]. It has also been reported that KMT2A regulates FOXM1 and SOX2 via KLF11, and KMT2A inhibition, leading to decreased spheroid formation ability in human gastric cancer cell lines [52].

NANOG is another transcription factor with its role in pluripotency and differentiation in embryogenesis [53]. NANOG promotes tumor formation, self-renewal, apoptosis, drug resistance, formation of angiogenesis and cancer stemness [54]. A recent study showed that FOXM1 mediated by OTUD7B plays a role in NANOG and SOX2 expression in TNBC cells, and its inhibition suppresses tumor spheroid sizes and expression of stemness markers such as CD44 and EPCAM [55]. In lung cancer, FOXM1 inhibition via FOXM1 shRNA and Genistein combination resulted in suppression of spheroid formation and NANOG expression [56]. Another study revealed FOXM1 and NANOG expressions are regulated by ALKBH5 in cisplatin resistant head and neck squamous cancer [57].

OCT4, a transcription factor that can induce pluripotency, has been shown in various cancers as an oncogenic target and may function in creating complexes with other transcription factors like SOX2, NANOG, and ABCG2 [58]. In the triple negative breast cancer in vitro tumor model, FOXM1 inhibition by shRNA decreased the size and frequency of spheroid formation and suppressed the OCT4 and NANOG expression via the YAP1 signaling pathway [59]. In embryonal carcinoma cells, FOXM1 has been reported to regulate OCT4, and inhibition of FOXM1 directly suppresses OCT4 and NANOG expression levels [60].

FOXM1 Sustains CSC Proliferation and Promotes Invasion and Migration

FOXM1 promotes cancer cell proliferation through its regulatory role in the cell cycle, with dysregulated FOXM1 being associated with increased mitosis [61,62]. Studies by Lou et al. revealed that FOXM1 induces G0/G1 to the S phase switch in Nasopharyngeal Cancer (NPC) cells while promoting in vivo tumor formation, in vitro spheroid formation and expression of stemness-related proteins, ABCG2, SOX2, NANOG and OCT4 [63]. FOXM1 is associated with tumor progression and shorter progression-free patient survival in ovarian cancer; in vitro studies with chemo-resistant IGROV1 ovarian cancer cells showed higher expression of stemness markers, CD44, SOX2 and NANOG, all in correlation with FOXM1 expression. Along with this finding FOXM1 overexpression promoted the same markers, CD44, SOX2, NANOG, and spheroid formation [64]. In the in vivo model of hepatocellular carcinoma (HCC), direct binding of FOXM1 to the promotor region of CD44 has been demonstrated, and FOXM1’s deletion significantly suppressed the tumor nodule formation, specifically the CD44, EPCAM expressing cell population [65]. In a liver cancer model, CD133+/ CD24+ cells were shown to have a higher capacity of stemness and FOXM1 expression. Inhibition of FOXM1 via siRNA in liver cancer stem cells (LCSCs) suppressed ki67 expression and reduced the proliferation, migration and invasion capacity of LCSCs. Also, researchers found that FOXM1 inhibition suppresses protein expression of N-Cadherin, E-Cadherin and Vimentin, which are associated with epithelial-mesenchymal-transition (EMT) [66]. FOXM1 is linked to β-catenin/Wnt pathway regulation and stemness in many studies [67-71]. Su et al. showed that CD133+/CD44+ lung cancer stem cells (LCSCs) have a higher capacity of tumor formation, and FOXM1 is upregulated in that subpopulation. Later, they found that FOXM1 plays a role as a downstream target of the β-catenin/Wnt pathway, and inhibition of FOXM1 via siRNA suppresses migration and invasion ability of LCSCs [71]. CENPU was found highly expressed in cervical cancer patients and in vitro analysis showed that CENPU regulates stemness markers, FOXM1/β-catenin/Wnt signaling, and its inhibition halts migration and invasion, while FOXM1 induction reverses the effects of CENPU inhibition [72]. In colorectal cancer, Valverde et al. used a combination of AEE788, a multiple kinase inhibitor, and Celecoxib, a COX2 inhibitor, and found that it suppresses FOXM1 expression, spheroid formation and migration ability [73].

The complexity of tumorigenesis is not only the result of many intrinsic regulations but also its interaction with the surrounding microenvironment, including the extracellular matrix, immune cells, fibroblasts, and epithelial cells [74]. The role of FOXM1 in CSCs and tumor microenvironment remains to be elucidated. Patient-derived ovarian CSCs (OCSCs) co- cultured in a 3D organotypic system showed higher FOXM1 expression and activity compared to OCSCs cultured without tumor microenvironment components. The FOXM1 inhibitor Thiostrepton reduced the viability of OCSCs and enhanced the effects of the PARP inhibitor Olaparib [75].

Due to their association with reduced therapeutic response, CSCs have been proposed as an essential target to overcome drug resistance [76]. ABC transporters play a role in drug efflux and cause multidrug resistance. Bergamaschi et al. demonstrated that FOXM1 is associated with tamoxifen resistance in ER positive breast cancer by driving the expression of ABC transporter ABCG2 and promoting spheroid formation [77]. In another breast cancer in vitro model using MDA-MB-231 and MCF7 cell lines, GDF-15 expression correlated with FOXM1, SOX2, OCT4, and ABCC5 expressions [78]. In nasopharyngeal cancer (NPC), it has been found that paclitaxel resistance correlates with higher FOXM1, CD44, ALDH1, SOX2, and ABCC5. FOXM1 inhibition with siRNA lowered the expression of ABCC5 and sensitized the NPC to paclitaxel [79]. In high-grade non-serous-epithelial ovarian cancer patients, FOXM1, was found to be highly expressed, and its expression correlated with the tumor grade and inhibition of FOXM1, whereby siRNA sensitized the cells to chemotherapeutic agents such as carboplatin, cisplatin and doxorubicin [80]. In another chemo-resistant ovarian cancer model, researchers showed that chemo resistance is linked to higher stemness capacity, and FOXM1 inhibition reduces stemness while inhibiting resistance to cisplatin [81]. In the pancreatic cancer in vitro model, Trametes Robiniophila Murr (Huaier) which suppresses FOXM1 expression, was shown to inhibit spheroid formation. In an in vivo breast cancer model, FOXM1 inhibition improved the effect of gemcitabine [82]. In the prostate cancer model, Yuan et al. showed that FOXM1 regulates stemness through UHTF1 gene transcription, which has been shown to play a role in docetaxel resistance [83]. Recently, Li et al. showed that another FOX- related protein, FBXO7, regulates stemness via exon Va inclusion of FOXM1. That process promotes a more stabilized version of FOXM, FOXM1c subtype, related to poor patient survival. Notably, inhibition of FBXO7 sensitizes the glioblastoma to temozolomide in vitro and in vivo [84].

Given its regulatory role on tumorigenesis, resistance to conventional therapies and influence on cancer stemness, FOXM1 represents a promising target for cancer treatment. Currently, no FDA-approved therapies specifically target FOXM1. Although several FOXM1 inhibitors have been identified, none have progressed to clinical trials due to a lack of potency and selectivity. Therefore, there is an urgent need for the development of potent, highly selective, and safe FOXM1 inhibitors. Bu et al. identified M1-20, an interfering protein and a FOXM1 transcription inhibitor, demonstrating its inhibitory effects on cervical cancer, TNBC, ER+ breast cancer, sarcoma and lung cancer cell lines. They found that FOXM1 inhibition suppresses the expression of stem cell markers ALDH1 and CD44 expression and enhances chemotherapy efficacy [85]. In osteosarcoma cells, small molecule inhibitors NSM00158 and NSC95397 showed regulatory effects on in vitro and in vivo tumor growth via CtBP1/FOXM1/MDR1 signaling axis, sensitizing the tumors to cisplatin chemotherapy [86]. Roca et al., demonstrated that Domatinostat (4SC-202), a selective HDAC small molecule inhibitor in clinical trials, suppresses FOXM1 mRNA expression and spheroid formation while sensitizing pancreatic cancer models to chemotherapy [87].

It was also found that AURKA, Aurora Kinase A, and FOXM1 overexpression promote stemness in breast cancer through a positive feedback mechanism. The novel AURKA inhibitor AKI603, in combination with the FOXM1 inhibitor Thiostrepton, synergistically suppressed in vitro spheroid formation and in vivo tumor formation, suggesting that combining FOXM1 inhibitors with AURORA inhibitors may overcome therapy resistance [88]. In a liver cancer in vitro model, Thiostrepton reduced sphere formation and the expression of CD44, SOX2 in regorafenib-resistant cells, indicating its potential to target stemness signatures [89]. Joshi et al., showed that Siomycin-A, a FOXM1 inhibitor, significantly reduced the spheroid formation capacity of cells derived from in vivo glioblastoma tumors compared to control groups. Siomycin-A combined with the chemotherapy agent Temozolomide suppressed in vivo tumor growth and reduced drug resistance in glioblastoma stem cell- induced tumors [90]. In hepatocellular carcinoma (HCC) in vitro models, Alfa-fetoprotein (AFP)-positive cells showed high expression of FOXM1. Carfilzomib, a proteasome inhibitor, inhibited the expression of FOXM1 and AFP. In the in vivo model, Carfilzomib combination with DC10, an anti-mouse VEGFR2 antibody, reduced the viability of tumors derived from AFP- positive cells [91]. In addition, Zhang et al. showed the effect of M-138, a recombinant protein constructed explicitly for FOMX1 N terminus inhibitory domain activation, on BC, HCC, lung cancer, and cervical adenocarcinoma cell lines. M-138 disturbed the interaction between FOXM1 and SMAD3, suppressed the in vivo tumor growth and OCT4, ALDH1 expression [92] [Table 1].

Table 1: FOXM1 Inhibitors with their effects on Cancer Stemness

FOXM1 is a commonly overexpressed oncogenic transcription factor linked to poor patient survival and is an emerging molecular target for cancer treatment, including CSCs. Many preclinical studies underline FOXM1’s regulatory effect on key transcription factors related to pluripotency, stemness, tumorigenesis, migration, invasion, epithelial mesenchymal transition, and drug resistance. Most notably, FOXM1 inhibition enhances the effect of chemotherapy and radiotherapy across various cancer models,making it a critical player in overcoming therapy resistance and suppressing tumor growth and progression. However, its effects on cancer stemness and the tumor microenvironment remains to be fully elucidated. The use of 3D-organoid models could provide clearer insights into its role in the near future. Additionally, the role of FOXM1 subtypes in stemness capacity is still unclear. Despite its potential as a molecular target in many cancer types, no FDA-approved targeted therapy for FOXM1 exists. Given its oncogenic importance, there is an urgent need to develop effective FOXM1 inhibitors. The identification of safe and effective FOXM1 inhibitors and their translation to the clinic may significantly impact the treatment of FOXM1-driven cancers and improve patient survival.

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