Investigation of FOXM1 as a Potential New Target for Melanoma

Abstract

Recent studies have shown that immunotherapies and molecular targeted therapies are effective for advanced melanoma. Non-antigen-specific immunotherapies such as immunocheckpoint blockades have been shown to be effective in the treatment of advanced melanoma. However, the response rates remain low. To improve their efficacy, they should be combined with antigen-specific immunotherapy. Elevated expression of the transcription factor, Forkhead box M1 (FOXM1), has been reported in various human cancers, and it has been shown to have potential as a target for immunotherapy. The purpose of this study was to investigate the FOXM1 expression in human melanoma samples and cell lines, to evaluate the relationship between the FOXM1 expression and the clinical features of melanoma patients and to investigate the association between the FOXM1 and MAPK and PI3K/AKT pathways in melanoma cell lines. We conducted the quantitative reverse transcription PCR (qRT-PCR) and Western blotting analyses of melanoma cell lines, and investigated melanoma and nevus tissue samples by qRT-PCR and immunohistochemistry. We performed MEK siRNA and PI3K/AKT inhibitor studies and FOXM1 siRNA studies in melanoma cell lines. We found that FOXM1 was expressed in all of the melanoma cell lines, and was expressed in 49% of primary melanomas, 67% of metastatic melanomas and 10% of nevi by performing immunohistochemical staining. Metastatic melanoma samples exhibited significantly higher mRNA levels of FOXM1 (p = 0.004). Primary melanomas thicker than 2 mm were also more likely to express FOXM1. Patients whose primary melanoma expressed FOXM1 had a significantly poorer overall survival compared to patients without FOXM1 expression (p = 0.024). Downregulation of FOXM1 by siRNA significantly inhibited the proliferation of melanoma cells, and blockade of the MAPK and PI3K/AKT pathways decreased the FOXM1 expression in melanoma cell lines. In conclusion, FOXM1 is considered to be a new therapeutic target for melanoma.

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

“…GO analysis of the RNA-seq revealed enrichment in pathways involved in cell division and proliferation (Figure S3C), consistent with the phenotypic effects of AMIGO2 knockdown. Interestingly, RPPA analysis did not show significant and/or consistent changes in components of the MAPK signaling pathway (Figure S3D), but did reveal significant changes in FOXM1 (Figures S3B and S3E; Table S3), a TF implicated in melanoma proliferation by promoting cell-cycle progression (Bhat et al, 2008; Ito et al, 2016; Miyashita et al, 2015). Thus, our profiling data suggest that AMIGO2 loss results in transcriptional changes affecting proliferation prior to cell death.…”

The Tumor Suppressive Role of MiRNA-509-5p by Targeting FOXM1 in Non-Small Cell Lung Cancer

“…Moreover, overexpression of FOXM1 has been linked in poor prognosis in many solid tumor types [7,36]. Previous studies show FOXM1 enhances cell cycle progression by promoting G1 to S and G2 to M phase transitions [37].…”

“…Aberrant expression of miRNAs occurs in many types of cancers, some of which function as tumor suppressor genes or oncogenes [6]. Some studies have implied that miRNAs act as crucial modulators for cancer cell migration, proliferation or epithelialmesenchymal transition (EMT) [7][8][9][10][11][12][13][14]. miR-509-5p has been demonstrated to inhibit EMTrelated genes in melanomas [15].…”

Effects of FOXM1 inhibition and ionizing radiation on melanoma cells

“…FOXM1 expression has been noted to be constitutively activated in many cancers including melanoma and to contribute to tumorigenesis and chemo-and radio-resistance (5,(7)(8)(9). A series of 10 melanoma cell lines were tested for FOXM1 protein expression by Western blotting with two different FOXM1 antibodies.…”

“…Recently several lines of evidence have lent support to the roles of FOXM1 expression in inducing metastatic melanoma and suppression of FOXM1 via RNA interference, blocking peptides, or chemotherapeutic agents has proven successful in countering tumorigenesis (7)(8)(9)(10). Importantly new evidence has indicated that combined treatment of FOXM1 inhibition with a small molecule inhibitor Siomycin A (SIOA) and irradiation can achieve a higher rate of cell death in glioblastoma cell lines, thus raising the possibility of harnessing FOXM1 inhibitors as a radiosensitizing agent (11).…”