Novel FOXM1 Inhibitor STL001 sensitizes different human cancers to broad spectrum of anticancer drugs
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE261182 | GEO | 2024/05/08
REPOSITORIES: GEO
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Project description:The transcription factor FOXM1 coordinates the expression of cell cycle-related genes and plays a pivotal role in tumorigenesis and cancer progression. We have previously shown that FOXM1 acts downstream of 14-3-3ζ signaling, which correlates with a more aggressive tumor phenotype. However, the role that FOXM1 might play in engendering the resistance to endocrine treatments in estrogen receptor-positive (ER+) patients when tumor FOXM1 is high, has not been clearly defined. To understand the role of FOXM1 in endocrine resistance and cancer aggressiveness, we analyzed FOXM1 protein expression by IHC in 501 ER-positive breast cancers; this revealed high FOXM1 expression in 20% of the tumors and a significantly reduced survival in these patients (p=0.003, log rank Mantel-Cox). We also mapped genome-wide FOXM1 binding events by chromatin immunoprecipitation, followed by high-throughput sequencing (ChIP-seq), in hormone-sensitive and resistant breast cancer cells after tamoxifen treatment. FOXM1 binding sites were enriched at the transcription start site of genes involved in cell cycle progression, maintenance of stem cell properties, and invasion and metastasis, all of which are correlated with the worst prognosis in ERα-positive patients treated with tamoxifen. Binding profiles were also integrated with gene expression data from cells before and after FOXM1 knockdown to highlight specific FOXM1 transcriptional networks. By modulating the levels of FOXM1 and newly discovered FOXM1-regulated genes [in breast cancer cells], we demonstrate that increased expression of FOXM1 was associated with an expansion of the cancer stem-like cell population and with increased cell invasiveness and resistance to endocrine treatments. Use of a selective FOXM1 inhibitor proved very effective in restoring endocrine therapy sensitivity and decreasing breast cancer aggressiveness. Collectively, our findings uncover novel roles for FOXM1 and FOXM1-regulated genes in promoting cancer stem-like cell properties and therapy resistance, and highlight the relevance of FOXM1 as a therapeutic target to be considered for reducing invasiveness and enhancing breast cancer response to endocrine treatments. MCF-7 human breast adenocarcinoma cells were tranfected with control, and FOXM1 siRNA for 72 hours and treated with 0.1% EtOH (Vehicle) or 1 uM TOT for 24 hours, and cDNA microarray analyses were carried out using Affymetrix [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array.
2014-08-07 | E-GEOD-55204 | biostudies-arrayexpress
Project description:The contribution of the majority of frequently mutated genes to tumourigenesis is not fully defined. Many aggressive human cancers, such as triple negative breast cancers (TNBCs), have a poor prognosis and lack tractable biomarkers and targeted therapeutic options. Here, we systematically characterize loss-of-function mutations to generate a functional map of novel driver genes in a 3-dimensional model of breast cancer heterogeneity that more readily recapitulates the unfavourable tumour microenvironment in vivo. This identified the histone acetyltransferase CREBBP as a potent tumour suppressor gene whose silencing provided a 3D-specific growth advantage only under oxygen and nutrient deplete conditions. CREBBP protein expression was altered in a substantial proportion of TNBCs as well as several other solid tumours, including endometrial, bladder, ovarian and squamous lung cancers. In multiple primary tumours and cell models, loss of CREBBP activity resulted in upregulation of the FOXM1 transcriptional network. Strikingly, treatment with a range of CDK4/6 inhibitors (CDK4/6i), that indirectly target FOXM1 activity, selectively impaired growth in both CREBBP-altered spheroids and cell line xenografts and patient derived models from multiple tumour types. This study is the first to provide rationale for CREBBP as a biomarker for CDK4/6i response in cancer representing a new treatment paradigm for tumours that harbour CREBBP alterations that have limited therapeutic options.
2022-03-23 | PXD012098 | Pride
Project description:FOXM1 transcription factor is an oncogene and a crucial regulator of cancer chemoresistance. Existing pharmacological FOXM1 inhibitors attenuate resistance of cancer cells to treatment but exhibit insufficient specificity. We performed in silico screening of small molecules from NIH LINCS database to identify STL427944 compound that suppresses FOXM1 through a novel two-step mechanism. STL427944 treatment induces relocalization of nuclear FOXM1 protein to cytoplasm, where it is subsequently degraded in an autophagosome-dependent manner. Human cancer cells treated with STL427944 exhibit increased sensitivity to cytotoxic effects of conventional chemotherapeutic agents. Transcriptome-based analysis of STL427944-induced gene expression changes revealed prominent suppression of gene signatures characteristic for FOXM1 and its downstream targets but no significant changes in other important regulatory pathways, thereby suggesting high selectivity of STL427944 towards FOXM1. We expect that STL427944 or its derivatives may be used in combination with different chemotherapeutical drugs to overcome tumor chemoresistance and improve anti-cancer treatment efficacy.
2021-07-21 | GSE162826 | GEO
Project description:FOXM1 plays a key role in M phase in normal cells and is overexpressed in human glioma. We found that FOXM1 deprivation could sensitize the glioma cells to TMZ chemotherapy. To find out the mechanistic regulation of FOXM1 in chemo-resistant genes, we used microarrays to select the potential genes regulated by FOXM1 which dominates in glioma chemo-resistance. U87 glioma cells were transiently transfected with none-target siRNA or FOXM1 siRNA. Total RNA were extracted after 48 hours and subjected to the microarray.
2012-08-10 | E-GEOD-40051 | biostudies-arrayexpress
Project description:Forkhead box M1 (FOXM1) is an oncogenic transcription factor overexpressed in many cancers and associated with aggressiveness. Using 1,1-diarylethylene-diammonium compounds that suppress FOXM1 activity, we utilized genome-wide transcriptomic, protein analyses, and functional approaches to identify mechanisms by which these compounds inhibit breast cancer growth and survival. These compounds downregulated FOXM1 gene networks in estrogen receptor (ER)-positive and triple negative breast cancer (TNBC) cells, and RNA-Seq and pathway analyses revealed that cell cycle progression, DNA damage repair, and apoptosis were most greatly affected, in agreement with the cancer promoting functions of FOXM1. TNBC and ER-positive breast cancer cells grown long-term with the inhibitors developed resistance. Notably, resistant cells showed transcriptional alterations and rewiring leading to reversal of the regulation of many genes in the FOXM1 network and marked changes in inflammatory signaling and HER2 and EGFR signature genes and pathways. High expression of a 43-gene Interferon-Related FOXM1 inhibitor resistance Signature (IRFMS) derived from ER-positive inhibitor resistant cells predicted a less good prognosis and poorer survival in patients with ER-positive breast cancer. Resistant cells showed greatly reduced ERα levels and responsiveness to fulvestrant and a 10-fold increased sensitivity to lapatinib, suggesting that targeting rewired processes in the resistant state may provide benefit and enable prolonged anticancer effectiveness.
2021-12-14 | GSE186682 | GEO
Project description:Forkhead box M1 (FOXM1) is an oncogenic transcription factor overexpressed in many cancers and associated with aggressiveness. Using 1,1-diarylethylene-diammonium compounds that suppress FOXM1 activity, we utilized genome-wide transcriptomic, protein analyses, and functional approaches to identify mechanisms by which these compounds inhibit breast cancer growth and survival. These compounds downregulated FOXM1 gene networks in estrogen receptor (ER)-positive and triple negative breast cancer (TNBC) cells, and RNA-Seq and pathway analyses revealed that cell cycle progression, DNA damage repair, and apoptosis were most greatly affected, in agreement with the cancer promoting functions of FOXM1. TNBC and ER-positive breast cancer cells grown long-term with the inhibitors developed resistance. Notably, resistant cells showed transcriptional alterations and rewiring leading to reversal of the regulation of many genes in the FOXM1 network and marked changes in inflammatory signaling and HER2 and EGFR signature genes and pathways. High expression of a 43-gene Interferon-Related FOXM1 inhibitor resistance Signature (IRFMS) derived from ER-positive inhibitor resistant cells predicted a less good prognosis and poorer survival in patients with ER-positive breast cancer. Resistant cells showed greatly reduced ERα levels and responsiveness to fulvestrant and a 10-fold increased sensitivity to lapatinib, suggesting that targeting rewired processes in the resistant state may provide benefit and enable prolonged anticancer effectiveness.
2021-12-14 | GSE186679 | GEO
Project description:The transcription factor FOXM1 coordinates the expression of cell cycle-related genes and plays a pivotal role in tumorigenesis and cancer progression. We have previously shown that FOXM1 acts downstream of 14-3-3ζ signaling, which correlates with a more aggressive tumor phenotype. However, the role that FOXM1 might play in engendering the resistance to endocrine treatments in estrogen receptor-positive (ER+) patients when tumor FOXM1 is high, has not been clearly defined. To understand the role of FOXM1 in endocrine resistance and cancer aggressiveness, we analyzed FOXM1 protein expression by IHC in 501 ER-positive breast cancers; this revealed high FOXM1 expression in 20% of the tumors and a significantly reduced survival in these patients (p=0.003, log rank Mantel-Cox). We also mapped genome-wide FOXM1 binding events by chromatin immunoprecipitation, followed by high-throughput sequencing (ChIP-seq), in hormone-sensitive and resistant breast cancer cells after tamoxifen treatment. FOXM1 binding sites were enriched at the transcription start site of genes involved in cell cycle progression, maintenance of stem cell properties, and invasion and metastasis, all of which are correlated with the worst prognosis in ERα-positive patients treated with tamoxifen. Binding profiles were also integrated with gene expression data from cells before and after FOXM1 knockdown to highlight specific FOXM1 transcriptional networks. By modulating the levels of FOXM1 and newly discovered FOXM1-regulated genes [in breast cancer cells], we demonstrate that increased expression of FOXM1 was associated with an expansion of the cancer stem-like cell population and with increased cell invasiveness and resistance to endocrine treatments. Use of a selective FOXM1 inhibitor proved very effective in restoring endocrine therapy sensitivity and decreasing breast cancer aggressiveness. Collectively, our findings uncover novel roles for FOXM1 and FOXM1-regulated genes in promoting cancer stem-like cell properties and therapy resistance, and highlight the relevance of FOXM1 as a therapeutic target to be considered for reducing invasiveness and enhancing breast cancer response to endocrine treatments.
2014-08-07 | GSE55204 | GEO
Project description:FOXM1 plays a key role in M phase in normal cells and is overexpressed in human glioma. We found that FOXM1 deprivation could sensitize the glioma cells to TMZ chemotherapy. To find out the mechanistic regulation of FOXM1 in chemo-resistant genes, we used microarrays to select the potential genes regulated by FOXM1 which dominates in glioma chemo-resistance.
2012-08-11 | GSE40051 | GEO
Project description:Here we showed that SOX7 was significantly downregulated in different cancer types, especially in lung and breast cancers. Low expression of SOX7 was associated with advanced stage of cancer with shorter overall survival. Cancer cells with loss of SOX7 promoted cell survival and colony formation, suppressed cellular apoptosis and produced a drug resistant phenotype against a variety of chemo/targeting therapeutic agents. Mechanistically, SOX7 induced cellular apoptosis through upregulation of genes associated with both P38 and apoptotic signaling pathway, as well as preventing the proteasome mediated degradation of pro-apoptotic protein BIM. Treatment of either a proteasome inhibitor MG132 or bortezomib, or with a p-ERK/MEK inhibitor U0126 attenuate the SOX7 promoted BIM degradation.
2022-05-08 | GSE130917 | GEO
Project description:Purpose：Forkhead box M1 (FOXM1) transcription factor is ubiquitously expressed in embryonic tissues but rare in differentiated cells. Increased expression of FOXM1 is observed in a variety of human malignancies. Here, we sought to characterize the expression and tumorigenic roles of FOXM1 in high-grade serous ovarian carcinoma (HGSOC). Experimental Design：TCGA dataset were analyed to identify potential master transcriptional regulators in HGSOC. Immunohistochemistry was performed to evaluate the clinical significance of FOXM1 in HGSOC. Invasion, clonogenic assays were conducted to determine to functional role of FOXM1. ChIP-seq and luciferase analyses were utilized to identify FOXM1 direct target genes in HGSOC. Association between mutant p53 and FOXM1 expression was investigated through TCGA data analysis, immunohistochemistry stainingand western blot. Results: We identified FOXM1 as a potential key transcription factor in ovarian cancer. FOXM1 was markedly increased in HGSOCs and high FOXM1 expression correlated with poor prognosis in HGSOC patients. Mechanistically, FOXM1 regulated CCNF and KIF20A at transcriptional level through binding on their promoters. Consistently, CCNF and KIF20A were elevated in HGSOCs and correlated with poor prognosis. Importantly, mutant p53 contribute to the high expression of FOXM1 in HGSOCs. Conclusions: These data reveal FOXM1 as a driver oncogenic transcription factor that promotes ovarian cancer malignancy which might be a potential drug target in HGSOC.
2021-12-01 | GSE142567 | GEO