STL427944 suppresses FOXM1 via nuclear export and subsequent autophagic degradation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE162826 | GEO | 2021/07/21
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.
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Project description:Rosmarinic acid methyl ester (RAME), a derivative of rosmarinic acid (RA), has been reported to have several therapeutic effects, including anti-tumor effects, against cervical cancer. However, its anti-tumor effects in ovarian cancer is unclear. In this study, we studied the molecular pathways associated with the anti-tumor effects of RAME in ovarian cancer. To identify the effects of RAME in ovarian cancer, RNA sequencing was performed in RAME-treated ovarian cancer cells; we found that RAME treatment downregulated genes closely involved with the target genes of the transcription factor Forkhead box M1 (FOXM1). It has been reported that FOXM1 is overexpressed in a variety of cancer cells and is associated with cell proliferation and tumorigenesis. Therefore, we hypothesized that FOXM1 is a key target of RAME; this can result in its anti-tumor effects. Treatment of ovarian cancer cells with RAME inhibited cell migration and invasion, as shown by wound healing and transwell migration assays. To examine whether RAME represses the action of FOXM1, we performed quantitative RT-PCR and ChIP-qPCR. Treatment of ovarian cancer cells with RAME decreased the mRNA expression of FOXM1 target genes and the binding of FOXM1 to its target genes. Moreover, FOXM1 expression was increased in cisplatin-resistant ovarian cancer cells, and combination treatment with RAME and cisplatin sensitized the cisplatin-resistant ovarian cancer cells, which was likely due to FOXM1 inhibition. Our research suggests that RAME is a promising option in treating ovarian cancer patients by revealing a novel molecular pathway underlying its anti-tumor effects.
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Project description:The forkhead transcription factor FOXM1 is a key regulator of the cell cycle and is overexpressed in cancer. Increased levels of FOXM1 are associated with both poor prognosis and oestrogen receptor (ERalpha) status in primary breast cancer. In this study, we map FOXM1 binding genome wide in both ERalpha-positive (MCF-7) and -negative (MDA-MB-231) breast cancer cells. We identify a common set of FOXM1 binding events at cell cycle-regulating genes, but in addition, in MCF-7 cells we find a high level of concordance with ERalpha-binding regions. FOXM1 binding at these co-binding sites is dependent on ERalpha binding, as depletion of ER protein levels reduced FOXM1 binding. FOXM1 interacts directly with both ERalpha co-activator CARM1 and is required for H3 arginine methylation at the ERalpha complex. Inhibition of FOXM1 activity with the ligand thiostrepton resulted in decreased FOXM1 binding at cca. 1400 sites genome wide and reduced expression of genes correlated with poor prognosis in ERalpha-positive tumour samples. These data demonstrate a novel role for the forkhead protein FOXM1 as an ERalpha cofactor and provide insight into the role of FOXM1 in ERalpha-positive breast cancer. MCF-7 cells were treated with either thiostrepton or DMSO for 6 hr. Each treatment was carried out in replicates of 6.
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Project description:Transcription factors (TFs) play a crucial role in diverse cellular physiology by controlling down-stream target genes. It has been well recognized that TFs are attractive target for treating human cancer since transcriptional activity or gene expression level of TFs can be directly modulated. To explore which TF functions as survival factor in human breast cancer, we applied gene expression data sets for survival analysis. We identified that FOXM1 is a potent oncogenic survival factor out of eleven TFs. Loss of FOXM1 function leads to breast cancer cells more sensitized to Doxorubicin (Dox). To investigate how FOXM1 sensitizes cancer cell in the presence of Dox, we carried out gene expression array experiment to monitor how down-stream target genes are changed by FOXM1. MDA-MB-231 cells were incubated with siLuc or siFOXM1. Thirty six hours later, cells were incubated with Dox (5micro mol) for 36 hrs. 3 siLuc., 3 siFOXM1, 3 siLuc and Dox treatment, 3 siFOXM1 and Dox treatment
2012-05-14 | E-GEOD-25741 | biostudies-arrayexpress
Project description:We sought to investigate the anticancer effects of the novel FOXM1 inhibitor, STL001 in a variety of human cancers from solid tumors including ovarian cancer, colorectal cancer, breast cancer, and prostate cancers. Here, the capacity of the novel compounds STL001 as FOXM1 inhibitor was verified in human cancer cell lines from solid tumors. Further, we showed here that FOXM1 inhibitor STL001 treatment resulted in sensitization of cancer cells to apoptotic death by multiple chemotherapeutic agents. STL001 was studied further to verify its direct target engagement with FOXM1. We have also provided Transcriptome-supported evidence that STL001 exhibits selectivity toward suppressing FOXM1-controlled regulatory pathways. This study verify and characterize a novel FOXM1 inhibitor STL001 that effectively antagonize FOXM1 activity and sensitize a variety of human cancer cells to traditionally used chemotherapy agents, and may be suitable for further clinical evaluation in targeting chemotherapy resistance human cancers.
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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.
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Project description:Doxorubicin (DOX) cardiotoxicity is an important factor of heart failure. The only clinically approved drug is dexrazoxane, while its side effect of secondary malignancies severely limited its application. It is urgent to find other alternative efficacious molecular for these chemotherapy patients. Colchicine is a safe and well tolerated anti-inflammation drug which also functions in attenuating the reactive oxygen species (ROS) generation. High dose of colchicine was reported block the autophagosome-lysosome fusion in cancer cells due to its destabilization effect to the microtubule system, while how colchicine affects the autophagic flux in cardiomyocytes is largely unknown. Recent years low dose of colchicine administration was reported helpful to the patients with pericarditis, postprocedural atrial fibrillation and coronary artery disease, most of the research attributed it to its anti-inflammation effect. Whether the autophagic flux regulated by colchicine also benefits to DOX induced heart failure remains unclear. Doxorubicin (DOX) administration was used to establish heart failure models in vivo and in vitro. Results showed that DOX blocked the autophagic vacuoles degradation, leading to damaged mitochondria and ROS accumulation. Heart failure characteristics were obviously improved after low dose of colchicine administration. Mechanistically, low dose of colchicine promoted the autolysosome degradation, cleared the damaged mitochondria, and ROS accumulation induced by the DOX and as a result attenuated DOX cardiotoxicity.
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Project description:The forkhead transcription factor FOXM1 is a key regulator of the cell cycle and is overexpressed in cancer. Increased levels of FOXM1 are associated with both poor prognosis and oestrogen receptor (ERalpha) status in primary breast cancer. In this study, we map FOXM1 binding genome wide in both ERalpha-positive (MCF-7) and -negative (MDA-MB-231) breast cancer cells. We identify a common set of FOXM1 binding events at cell cycle-regulating genes, but in addition, in MCF-7 cells we find a high level of concordance with ERalpha-binding regions. FOXM1 binding at these co-binding sites is dependent on ERalpha binding, as depletion of ER protein levels reduced FOXM1 binding. FOXM1 interacts directly with both ERalpha co-activator CARM1 and is required for H3 arginine methylation at the ERalpha complex. Inhibition of FOXM1 activity with the ligand thiostrepton resulted in decreased FOXM1 binding at cca. 1400 sites genome wide and reduced expression of genes correlated with poor prognosis in ERalpha-positive tumour samples. These data demonstrate a novel role for the forkhead protein FOXM1 as an ERalpha cofactor and provide insight into the role of FOXM1 in ERalpha-positive breast cancer. The FOXM1-binding sites were mapped by ChIP-Seq in MCF-7 and MDA-MB-231 cells. Cells were treated either with thiostrepton, a FOXM1 inhibitor, or with DMSO (as control). Four replicates were performed in MCF7 cells and two replicates in MDA-MB-231 cells.
2013-01-07 | E-GEOD-40762 | biostudies-arrayexpress
Project description:Autophagic flux is associated with chemoresistance, the leading cause of chemotherapeutic failure. Here, we showed that HAX-1 promotes chemoresistance by effectively blocking the fusion of autophagosomes with lysosomes. Mass spectrometric and functional studies demonstrated that HAX-1 recruited NEDD4 to promote Rab7a degradation and inhibited the binding of Rab7a with SNAREs by competitively binding to it. Furthermore, HAX-1 could bind to IGF2BP1 mRNA, thereby contributing to its stability and translation. Moreover, IGF2BP1 enhanced HAX-1 m6A methylation, thereby enhancing its stability. Via in vivo and in vitro experiments, we confirmed the positive role of the IGF2BP1-HAX-1 feedback loop in chemoresistance. Our data provide evidence that HAX-1, IGF2BP1, and SQSTM1 levels are useful predictors of clinical outcome and chemoresistance risk. In addition, our data provide new insights into the clinical applications of therapies related to autophagic flux and its associated molecular network in targeting cisplatin chemoresistance in nasopharyngeal carcinoma.
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