Prognostic significance of forkhead box M1 (FoxM1) expression and antitumour effect of FoxM1 inhibition in melanoma

Ito, Takamichi; Kohashi, Kenichi; Yamada, Yuichi; Maekawa, Akira; Kuda, Masaaki; Furue, Masutaka; Oda, Yoshinao

doi:10.1111/his.12909

Cited by 28 publications

(20 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Overexpression of the pleiotropic transcription factor FOXM1 has been observed in many human malignancies and regulates multiple pathways important for tumorigenesis (5,6). Recent studies demonstrate FOXM1 overexpression in malignant melanoma and an association with cancer stage and prognosis suggesting FOXM1 knockdown may be a novel therapeutic target (7)(8)(9). Consistent with these studies, we observed reduction in FOXM1 at micromolar Siomycin A doses in the metastatic melanoma cell line, SK-MEL-28, with a rather rapid drop-off in FOXM1 expression at concentrations above 1 µM.…”

Section: Discussionsupporting

confidence: 90%

“…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.…”

Section: Constitutive Foxm1 Expression In Melanoma Cell Linesmentioning

confidence: 99%

“…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).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effects of FOXM1 inhibition and ionizing radiation on melanoma cells

et al. 2018

View full text Add to dashboard Cite

Metastatic melanoma can be highly refractory to conventional radiotherapy and chemotherapy but combinatorial-targeted therapeutics are showing greater promise on improving treatment efficacy. Previous studies have shown that knockdown of Forkhead box M1 (FOXM1) can sensitize various tumor types to radiation-induced cell death. The effect of combining radiation with a small molecule FOXM1 inhibitor, Siomycin A, on growth, death and migration of a metastatic melanoma cell line (SK-MEL-28) that overexpresses this pleiotropic cell cycle regulator was investigated. Siomycin A (SIOA) was found to be a strong inducer of apoptosis, and inhibitor of proliferation and migration in a scratch wound assay in this cell line. Induction of apoptosis occurred at concentrations >1 µM in association with reductions in the constitutive FOXM1 and anti-apoptotic B-cell lymphoma 2 protein levels found in these cells. Single doses of ionizing radiation (0-40 Gy) delivered by linear accelerator caused inhibition of growth and migration without significant induction of cell death. Pretreatment with SIOA did not increase the sensitivity of this melanoma cell line to radiation as observed in other tumor types. These data confirm that as a single agent, SIOA is an effective inducer of cell death and inhibitor of migration in metastatic melanoma cells expressing constitutive FOXM1. In combination with radiation, SIOA pre-treatment, however, may not be of added benefit.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Constitutive Foxm1 Expression In Melanoma Cell Linesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of FOXM1 inhibition and ionizing radiation on melanoma cells

et al. 2018

View full text Add to dashboard Cite

show abstract

“…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.…”

Section: Resultsmentioning

confidence: 99%

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

et al. 2017

View full text Add to dashboard Cite

SUMMARY Bromodomain and extraterminal domain inhibitors (BETi) represent promising therapeutic agents for metastatic melanoma, yet their mechanism of action remains unclear. Here we interrogated the transcriptional effects of BETi and identified AMIGO2, a trans-membrane molecule, as a BET target gene essential for melanoma cell survival. AMIGO2 is upregulated in melanoma cells and tissues compared to human melanocytes and nevi, and AMIGO2 silencing in melanoma cells induces G1/S arrest followed by apoptosis. We identified the pseudokinase PTK7 as an AMIGO2 interactor whose function is regulated by AMIGO2. Epigenomic profiling and genome editing revealed that AMIGO2 is regulated by a melanoma-specific BRD2/4-bound promoter and super-enhancer configuration. Upon BETi treatment, BETs are evicted from these regulatory elements, resulting in AMIGO2 silencing and changes in PTK7 proteolytic processing. Collectively, this study uncovers mechanisms underlying the therapeutic effects of BETi in melanoma and reveals the AMIGO2-PTK7 axis as a targetable pathway for metastatic melanoma.

show abstract

“…All formalin-fixed (24 h in 10% buffered formalin) and paraffin-embedded (i.e., formalin-fixed paraffin-embedded (FFPE)) tissues were obtained from our hospital's archives. IHC staining was performed as reported previously [16][17][18][19][20]. Briefly, the archival FFPE tissue blocks were cut into 4-µm-thick tissue sections and then deparaffinized and rehydrated.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

Ito

Kaku-Ito

Murata

et al. 2020

JCM

Self Cite

View full text Add to dashboard Cite

Acral melanoma, a distinct form of cutaneous melanoma originating in the glabrous skin of the palms, soles, and nail beds, has a different genetic background from other subtypes of cutaneous melanoma. The roles of oncogenic BRAF mutations of acral melanoma in pathogenesis and patient outcomes have not been fully elucidated. We retrieved a total of 112 patients with primary acral melanoma and checked their BRAF V600E status using immunohistochemical staining of VE1 antibody. Among these cases, 21 acral melanoma samples (18.8%) showed positive BRAF V600E staining, and of those, 11 samples (9.8%) showed a heterogeneous staining pattern, with a mixture of VE1-positive and VE1-negative cells. BRAF V600E positivity was significantly associated with thicker melanoma (p = 0.0015). There was no significant difference in clinicopathological factors between homogeneous and heterogeneous VE1-positive acral melanoma. Both patients with BRAF V600E-positive acral melanoma and those with heterogeneous BRAF V600E had significantly shorter melanoma-specific survival than those with BRAF V600E-negative melanoma in Kaplan–Meier analysis (p = 0.0283 and p = 0.0065, respectively). These findings provide novel insights into the pathobiology of acral melanoma.

show abstract

Prognostic significance of forkhead box M1 (FoxM1) expression and antitumour effect of FoxM1 inhibition in melanoma

Abstract: We have shown the prognostic impact of FoxM1 on melanoma patients. FoxM1 inhibition may be a potential therapeutic option for advanced melanoma.

Cited by 28 publications

References 23 publications

Effects of FOXM1 inhibition and ionizing radiation on melanoma cells

Effects of FOXM1 inhibition and ionizing radiation on melanoma cells

Harnessing BET Inhibitor Sensitivity Reveals AMIGO2 as a Melanoma Survival Gene

Immunohistochemical BRAF V600E Expression and Intratumor BRAF V600E Heterogeneity in Acral Melanoma: Implication in Melanoma-Specific Survival

Contact Info

Product

Resources

About