• CP: Stem cell research
• EWS::FLI1
• Ewing sarcoma
• IGF-1/insulin signaling
• YAP1/TAZ signaling
• endochondral bone development
• mesenchymal stem cells
• puberty

• Mesenchymal Stem Cells/metabolism
• Mesenchymal Stem Cells/pathology
• Animals
• Proto-Oncogene Protein c-fli-1/metabolism
• Proto-Oncogene Protein c-fli-1/genetics
• YAP-Signaling Proteins
• Insulin-Like Growth Factor I/metabolism
• Insulin-Like Growth Factor I/pharmacology
• RNA-Binding Protein EWS/metabolism
• RNA-Binding Protein EWS/genetics
• Cell Transformation, Neoplastic/metabolism
• Cell Transformation, Neoplastic/pathology
• Cell Transformation, Neoplastic/genetics
• Mice
• Adaptor Proteins, Signal Transducing/metabolism
• Adaptor Proteins, Signal Transducing/genetics
• Humans
• Sarcoma, Ewing/pathology
• Sarcoma, Ewing/metabolism
• Sarcoma, Ewing/genetics
• Transcription Factors/metabolism
• Oncogene Proteins, Fusion/metabolism
• Oncogene Proteins, Fusion/genetics
• Cellular Reprogramming/drug effects
• Cell Cycle Proteins
• Phosphoproteins/metabolism

• EWS-FLI1
• Ewing sarcoma
• chimeric fusion protein
• emerging alternative targets
• gene translocation
• pediatric cancer

• CD99
• EWS::FLI1
• Ewing sarcoma
• biomarkers
• transcriptome
• tumor growth

• Fondazione AIRC per la ricerca sul cancro ETS

• FOXM1
• cIAP2
• cell cycle
• chemoresistance
• epithelioid sarcoma

• Forkhead Box Protein M1/metabolism
• Forkhead Box Protein M1/genetics
• Humans
• Sarcoma/metabolism
• Sarcoma/drug therapy
• Sarcoma/genetics
• Forkhead Transcription Factors/metabolism
• Forkhead Transcription Factors/genetics
• Thiostrepton/pharmacology
• Female
• Male
• Cell Line, Tumor
• Middle Aged
• Adult
• Adolescent
• Young Adult
• Aged
• RNA, Small Interfering/metabolism
• Cell Proliferation/drug effects
• Immunohistochemistry
• Child

• EWS/FLI1
• Ewing sarcoma target genes
• therapeutic opportunities

• Adolescent
• Adult
• Humans
• Bone Neoplasms/therapy
• Bone Neoplasms/drug therapy
• Cell Line, Tumor
• Epigenesis, Genetic
• Gene Expression Regulation, Neoplastic
• Oncogene Proteins, Fusion/genetics
• Oncogene Proteins, Fusion/metabolism
• Proteins/metabolism
• Proto-Oncogene Protein c-fli-1/genetics
• Proto-Oncogene Protein c-fli-1/metabolism
• RNA-Binding Protein EWS/genetics
• RNA-Binding Protein EWS/metabolism
• Sarcoma, Ewing/therapy
• Sarcoma, Ewing/drug therapy
• Tumor Microenvironment

• 2021-R1A4A1031574 National Research Foundation of Korea

• Cell Cycle Proteins/metabolism
• Child
• DNA
• DNA-Binding Proteins/genetics
• Gene Expression Regulation, Neoplastic
• Humans
• Nuclear Proteins/genetics
• Oncogene Proteins, Fusion/metabolism
• Proto-Oncogene Protein c-fli-1/genetics
• Proto-Oncogene Protein c-fli-1/metabolism
• RNA-Binding Protein EWS/genetics
• RNA-Binding Protein EWS/metabolism
• Sarcoma, Ewing/pathology
• Transcription Factors/genetics
• Transcription Factors/metabolism

• Japan Society for the Promotion of Science
• Takeda Science Foundation

• Antibacterial drug
• Anticancer
• Antimalaria
• Molecular target
• Signalling pathway
• Thiostrepton

• Fox factors-based therapeutics
• Fox family
• bone diseases
• bone metabolism
• signaling pathways

• National Natural Science Foundation of China

• Cell cycle
• FANCD2
• FOXM1
• Malignant rhabdoid tumor
• NBS1

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Apoptosis/genetics
• Cell Cycle Checkpoints/drug effects
• Cell Cycle Checkpoints/genetics
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Movement/genetics
• Cell Proliferation/drug effects
• Cell Proliferation/genetics
• DNA Damage/drug effects
• DNA Damage/genetics
• Down-Regulation/drug effects
• Down-Regulation/genetics
• Fanconi Anemia Complementation Group D2 Protein/genetics
• Female
• Forkhead Box Protein M1/antagonists & inhibitors
• Forkhead Box Protein M1/genetics
• Gene Expression Regulation, Neoplastic/drug effects
• Gene Expression Regulation, Neoplastic/genetics
• Humans
• Immunohistochemistry/methods
• Infant
• Male
• Nuclear Proteins/genetics
• Prognosis
• RNA, Messenger/genetics
• RNA, Small Interfering/genetics
• Rhabdoid Tumor/drug therapy
• Rhabdoid Tumor/genetics
• Survival Rate
• Thiostrepton/pharmacology

Osteosarcoma is a common primary bone cancer that there are currently no effective treatment strategies for. Forkhead box M1 (FoxM1) is key in the development of osteosarcoma, and microRNA (miR)-216b serves an antitumor role by targeting FoxM1. Moreover, thiostrepton (TST), a natural thiazole antibiotic, induces antitumor effects and specifically targets FoxM1. Therefore, the present study investigated whether thiostrepton and miR-216b synergistically inhibited osteosarcoma cells by targeting FoxM1. The MTT assay, reverse transcription-quantitative PCR, a dual-luciferase reporter assay and flow cytometry were performed. Compared with the human osteoblast cell line hFOB1.19, miR-216b expression was significantly downregulated in the osteosarcoma cell lines U2OS, MG63 and Saos-2. By contrast, FoxM1 expression was significantly upregulated in osteosarcoma cell lines compared with the hFOB1.19 cell line. The results indicated that miR-216b targeted the 3′-untranslated region of FoxM1. Moreover, the results suggested that miR-216b cooperated with TST to decrease cell cytotoxicity and increase cell apoptosis. In addition, miR-216b cooperated with TST to increase Bax expression and decrease Bcl-2 expression. In conclusion, the combination of TST and miR-216b synergistically promoted osteosarcoma cell cytotoxicity and apoptosis by targeting FoxM1. Therefore, the present study suggested that the combination of TST and miR-216b may serve as a promising therapeutic strategy for osteosarcoma.

• forkhead box M1
• microRNA-216b
• osteosarcoma
• thiostrepton

Osteosarcoma (OS) is a highly aggressive bone malignancy that is mostly diagnosed in children and young adults. Increasing evidence indicates that the transcription factor Forkhead Box M1 (FoxM1) plays a key role in the pathogenesis of various tumors. However, the function of FoxM1 in OS has not been clearly elucidated.

In the present study, we first analyzed the expressions of FoxM1 in human OS and myositis ossificans (MO, included as a control) tissues by immunohistochemistry. To investigate the functional significance of FoxM1 in OS tumorigenesis, we examined the effects of FoxM1 downregulation in MG-63 and HOS-MNNG cells by either short hairpin RNA (shRNA)-mediated gene silencing or treatment with thiostrepton, a specific FoxM1 inhibitor.

FoxM1 was detected in 82.1% (55/67) of OS vs only 10% (2/20) of MO samples. High expressions of FoxM1 were also detected in three human OS cell lines (HOS-MNNG, MG-63, and U-2OS). FoxM1 downregulation significantly reduced MG-63 and HOS-MNNG cell proliferation, migration, and invasion as well as cell cycle arrest in the G2/M phase and increased apoptotic cell death.

The present study demonstrated the critical role of FoxM1 in the pathogenesis of OS. Therefore, FoxM1 may serve as a potential therapeutic target for the treatment of OS.

• FoxM1
• osteosarcoma
• shRNA
• thiostrepton
• tumorigenesis

Ewing sarcoma (ES) family of tumors includes bone and soft tissue tumors that are often characterized by a specific translocation between chromosome 11 and 22, resulting in the EWS-FLI1 fusion gene. With the advent of multi-modality treatment including cytotoxic chemotherapy, surgery, and radiation therapy, the prognosis for patients with ES has substantially improved. However, a therapeutic plateau is now reached for both localized and metastatic disease over the last two decades. Burdened by the toxicity limits associated with the current frontline systemic therapy, there is an urgent need for novel targeted therapeutic strategies. In this review, we discuss the current treatment paradigm of ES, and explore preclinical evidence and emerging treatments directed at tumor signaling pathways and immune targets.

• Ewing sarcoma
• antibodies
• immunotherapy
• pediatric sarcomas
• targeted therapy

• Angiomatoid fibrous histiocytoma
• Clear cell sarcoma
• Desmoplastic small round cell tumor
• EWSR1
• EWSR1–NFATC2
• Myoepithelial tumor
• Myxoid liposarcoma
• Sarcoma

• Biomarkers, Tumor/genetics
• Gene Rearrangement/physiology
• Humans
• Mesenchymoma/classification
• Mesenchymoma/genetics
• Mesenchymoma/pathology
• Oncogene Proteins, Fusion/genetics
• RNA-Binding Protein EWS/genetics
• Soft Tissue Neoplasms/classification
• Soft Tissue Neoplasms/genetics
• Soft Tissue Neoplasms/pathology
• Translocation, Genetic

• Forkhead Box M1 (FOXM1)
• U2OS
• diallyl disulfide (DADS)
• invasion
• miR-134
• osteosarcoma (OS)
• proliferation

Ewing Sarcoma is an aggressive malignant neoplasm affecting children and young adults. Ewing Sarcoma is driven by transcription factor fusion oncoproteins, most commonly EWS/Fli1. While some patients can be cured with high-dose, multi-agent, chemotherapy, those that cannot currently have few options. Targeting of the driver oncofusion remains a logical therapeutic approach, but has proven difficult. Recent work has pointed to epigenetic mechanisms as key players, and potential new therapeutic targets, in Ewing Sarcoma. In this study we examined the activity of the pan-JHDM pharmacologic inhibitor JIB-04 in this disease. We show that JIB-04 potently inhibits the growth and viability of Ewing Sarcoma cells, and also impairs tumor xenograft growth. Effects on histone methylation at growth-inhibitory doses vary among cell lines, with most cell lines exhibiting increased total H3K27me3 levels, and some increased H3K4me3 and H3K9me3. JIB-04 treatment widely alters expression of oncogenic and tumor suppressive pathways, including downregulation of known oncogenic members of the Homeobox B and D clusters. JIB-04 also disrupts the EWS/Fli1 expression signature, including downregulation of pro-proliferative pathways normally under positive oncofusion control. Interestingly, these changes are accompanied by increased levels of the EWS/Fli1 oncofusion, suggesting that the drug could be uncoupling EWS/Fli1 from its oncogenic program. All Ewing Sarcoma cell lines examined also manifest increased DNA damage upon JIB-04 treatment. Together, the findings suggest that JIB-04 acts via multiple mechanisms to compromise Ewing Sarcoma cell growth and viability.

• Ewing Sarcoma
• Jumonji
• demethylase
• epigenetics
• inhibitor

Breast cancer (BC) is the most common cause of cancer-related death in females in Saudi Arabia. BC in Saudi women tend to behave more aggressively than breast cancer in the West. Therefore, identification of new molecular targets and treatment strategies are highly warranted to improve patient outcome. FoxM1 has been shown to play a critical role in pathogenesis of various malignancies. In this study, we explored the prevalence and clinical implication of FoxM1 overexpression in Saudi breast cancer. FoxM1 protein overexpression was seen in 79% (770/975) of BC tissues and was associated with aggressive clinical parameters such as younger age (< 30 yrs) (p = 0.0172), high grade (p < 0.0001), mucinous histology (p < 0.0001) and triple negative phenotype (p < 0.0001). Overexpression of FoxM1 was significantly associated with activated AKT (p < 0.0001), Ki67 expression (p < 0.0001), VEGF (p < 0.0001), MMP-9 (p < 0.0001), XIAP (p < 0.0001) and Bcl-xL (p = 0.0300). Importantly, FoxM1 overexpression is found to be an independent prognostic marker in multivariate analysis in advanced stage (Stage III and IV) breast cancer (p = 0.0298). In vitro data using BC cell lines showed that down-regulation of FoxM1 using specific inhibitor, thiostrepton or siRNA inhibited cell migration, invasion and angiogenesis. In addition, treatment of BC cell lines with thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. In vivo, thiostrepton treatment regressed MDA-MB-231 cells generated xenografts via down-regulation of FoxM1 and its downstream targets. Our results suggest that FoxM1 may be a potential therapeutic target for the treatment of aggressive breast cancers.

• FoxM1
• apoptosis
• breast cancer
• invasion
• thiostrepton

• EWS/Fli1
• Ewing sarcoma
• JQ1
• bromodomain
• epigenetic

FOXM1 is a pro-proliferative transcription factor that promotes cell cycle progression at the G1-S, and G2-M transitions. It is activated by phosphorylation usually mediated by successive cyclin – cyclin dependent kinase complexes, and is highly expressed in sarcoma. p53 down regulates FOXM1 and FOXM1 inhibition is also partly dependent on Rb and p21. Abnormalities of p53 or Rb are frequent in sporadic sarcomas with bone or soft tissue sarcoma, accounting for 36% of index cancers in the high penetrance TP53 germline disorder, Li-Fraumeni syndrome.

FOXM1 stimulates transcription of pluripotency related genes including SOX2, KLF4, OCT4, and NANOG many of which are important in sarcoma, a disorder of mesenchymal stem cell/ partially committed progenitor cells. In a selected specific, SOX2 is uniformly expressed in synovial sarcoma. Embryonic pathways preferentially used in stem cell such as Hippo, Hedgehog, and Wnt dominate in FOXM1 stoichiometry to alter rates of FOXM1 production or degradation. In undifferentiated pleomorphic sarcoma, liposarcoma, and fibrosarcoma, dysregulation of the Hippo pathway increases expression of the effector co-transcriptional activator Yes-Associated Protein (YAP). A complex involving YAP and the transcription factor TEAD elevates FOXM1 in these sarcoma subtypes. In another scenario 80% of desmoid tumors have nuclear localization of β-catenin, the Wnt pathway effector molecule. Thiazole antibiotics inhibit FOXM1 and because they have an auto-regulator loop FOXM1 expression is also inhibited. Current systemic treatment of sarcoma is of limited efficacy and inhibiting FOXM1 represents a potential new strategy.

• DREAM
• FOXM1
• mesenchyme
• pluripotency genes
• thiazole antibiotics

• Chromosomal translocations
• Fusion genes
• Sarcomas
• Therapeutic strategies

Eukaryotic elongation factor 2 kinase (eEF2K), an emerging molecular target for cancer therapy, contributes to cancer proliferation, cell survival, tumorigenesis, and invasion, disease progression and drug resistance. Although eEF2K is highly up-regulated in various cancers, the mechanism of gene regulation has not been elucidated. In this study, we examined the role of Forkhead Box M1 (FOXM1) proto-oncogenic transcription factor in triple negative breast cancer (TNBC) cells and the regulation of eEF2K. We found that FOXM1 is highly upregulated in TNBC and its knockdown by RNA interference (siRNA) significantly inhibited eEF2K expression and suppressed cell proliferation, colony formation, migration, invasion and induced apoptotic cell death, recapitulating the effects of eEF2K inhibition. Knockdown of FOXM1 inhibited regulators of cell cycle, migration/invasion and survival, including cyclin D1, Src and MAPK-ERK signaling pathways, respectively. We also demonstrated that FOXM1 (1B and 1C isoforms) directly binds to and transcriptionally regulates eEF2K gene expression by chromatin immunoprecipitation (ChIP) and luciferase gene reporter assays. Furthermore, in vivo inhibition of FOXM1 by liposomal siRNA-nanoparticles suppressed growth of MDA-MB-231 TNBC tumor xenografts in orthotopic models. In conclusion, our study provides the first evidence about the transcriptional regulation of eEF2K in TNBC and the role of FOXM1 in mediating breast cancer cell proliferation, survival, migration/invasion, progression and tumorgenesis and highlighting the potential of FOXM1/eEF2K axis as a molecular target in breast and other cancers.

• FOXM1
• TNBC
• breast cancer
• eEF2-kinase
• triple-negative breast cancer

To identify neuron-selective androgen receptor (AR) signaling inhibitors, which could be useful in the treatment of spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, a neuromuscular disorder in which deterioration of motor neurons leads to progressive muscle weakness.

Cell lines representing prostate, kidney, neuron, adipose, and muscle tissue were developed that stably expressed the CFP-AR-YFP FRET reporter. We used these cells to screen a library of small molecules for cell type-selective AR inhibitors. Secondary screening in luciferase assays was used to identify the best cell-type specific AR inhibitors. The mechanism of action of a neuron-selective AR inhibitor was examined in vitro using luciferase reporter assays, immunofluorescence microscopy, and immunoprecipitations. Rats were treated with the most potent compound and tissue-selective AR inhibition was examined using RT-qPCR of AR-regulated genes and immunohistochemistry.

We identified the thiazole class of antibiotics as compounds able to inhibit AR signaling in a neuronal cell line but not a muscle cell line. One of these antibiotics, thiostrepton is able to inhibit the activity of both wild type and polyglutamine expanded AR in neuronal GT1-7 cells with nanomolar potency. The thiazole antibiotics are known to inhibit FOXM1 activity and accordingly, a novel FOXM1 inhibitor FDI-6 also inhibited AR activity in a neuron-selective fashion. The selective inhibition of AR is likely indirect as the varied structures of these compounds would not suggest that they are competitive antagonists. Indeed, we found that FOXM1 expression correlates with cell-type selectivity, FOXM1 co-localizes with AR in the nucleus, and that shRNA-mediated knock down of FOXM1 reduces AR activity and thiostrepton sensitivity in a neuronal cell line. Thiostrepton treatment reduces FOXM1 levels and the nuclear localization of beta-catenin, a known co-activator of both FOXM1 and AR, and reduces the association between beta-catenin and AR. Treatment of rats with thiostrepton demonstrated AR signaling inhibition in neurons, but not muscles.

Our results suggest that thiazole antibiotics, or other inhibitors of the AR-FOXM1 axis, can inhibit AR signaling selectively in motor neurons and may be useful in the treatment or prevention of SBMA symptoms.

• Androgen receptor
• Selective androgen receptor modulator
• Spinal and bulbar muscular atrophy
• Kennedy’s disease

Extraskeletal Ewing’s sarcoma/peripheral primitive neuroectodermal tumor (E-EWS/pPNET) is a rare aggressive malignant small round cell tumor. In this report, we present the case of a 15-year-old boy who suffered from acute abdominal pain accompanied by hematemesis and melena, and was eventually diagnosed with E-EWS/pPNET. To date, there have been only five reported cases of E-EWS/pPNET of the small bowel including the patient in this report. To the best of our knowledge, this is the first documentation of a pPNET of the small bowel mesentery at nonage. All these have made this report rare and significant.

• Extraskeletal Ewing’s sarcoma
• Peripheral primitive neuroectodermal tumor
• Nonage
• Small bowel mesentery
• Spontaneous rupture

• E-cadherin
• caveolin-1
• colorectal cancer
• foxM1

Synovial sarcoma (SS) is a soft tissue sarcoma of unknown histogenesis. Most metastatic or unresectable cases are incurable. Novel antitumor agents and precise prognostication are needed for SS patients. The protein forkhead box M1 (FOXM1), which belongs to the FOX family of transcription factors, is considered to be an independent predictor of poor survival in many cancers and sarcomas, but the prognostic implications and oncogenic roles of FOXM1 in SS are poorly understood. Here we examined the correlation between FOXM1 expression and clinicopathologic and prognostic factors, and we investigated the efficacy of FOXM1 target therapy in SS cases.

Immunohistochemical study of 106 tumor specimens was conducted to evaluate their immunohistochemical expression of FOXM1. An in vitro study examined the antitumor effect of the FOXM1 inhibitor thiostrepton and small interference RNA (siRNA) on two SS cell lines. We also assessed the efficacy of the combined use of doxorubicin (DOX) and thiostrepton.

Univariate and multivariate analyses revealed that FOXM1 expression was associated with poor prognosis in SS. The cDNA microarray analysis using clinical samples revealed that the expression of cell cycle-associated genes was correlated with FOXM1 expression. FOXM1 inhibition by thiostrepton showed significant antitumor activity on the SS cell lines in vitro. FOXM1 interruption by siRNA increased the chemosensitivity for DOX in both SS cell lines.

FOXM1 expression is a novel biomarker, and its inhibition is a potential treatment option for SS.

The online version of this article (doi:10.1186/s12885-016-2542-4) contains supplementary material, which is available to authorized users.

• Forkhead box M1 (FOXM1)
• Synovial sarcoma
• Thiostrepton

• Chromosomal translocation
• Ewing sarcoma
• Molecular pathogenesis

Leiomyosarcoma (LMS) of soft tissue is a sarcoma with smooth‐muscle differentiation, and conventional chemotherapy does not improve its outcome. The application of novel antitumor agents and precise prognostication has been demanded. The expression of the protein Forkhead box M1 (FOXM1), a member of the FOX family, is considered an independent predictor of poor survival in many cancers and sarcomas. However, the expression status of FOXM1 in LMS is poorly understood. The purposes of this study were to examine the correlation between the expression of FOXM1 and clinicopathologic or prognostic factors and to clarify the efficacy of FOXM1 target therapy in LMS. We evaluated the immunohistochemical expressions of FOXM1 using 123 LMS tumor specimens. Univariate and multivariate survival analyses revealed that FOXM1 expression was associated with poor prognosis in LMS. An in vitro study was then carried out to examine the antitumor effect of a FOXM1 inhibitor (thiostrepton) and siRNA on a novel LMS cell line, TC616. We also assessed the efficacy of the combined use of doxorubicin and thiostrepton. Thiostrepton showed dose‐dependent antitumor activity and TC616 cells treated with the combination of thiostrepton and doxorubicin showed lower proliferation compared to those treated with either drug individually. FOXM1 interruption by siRNA decreased cell proliferation and increased chemosensitivity. In conclusion, FOXM1 has potential to be a therapeutic target for LMS.

• FOXM1
• immunohistochemistry
• leiomyosarcoma
• prognosis
• thiostrepton

• dacarbazine
• forkhead box M1
• melanoma
• prognosis
• thiostrepton

• FOXM1
• Prognosis
• Rhabdomyosarcoma
• VEGF

Ewing sarcoma is an aggressive bone malignancy that affect children and young adults. Ewing sarcoma is the second most common primary bone malignancy in pediatric patients. Although significant progress has been made in the treatment of Ewing sarcoma since it was first described in the 1920s, in the last decade survival rates have remained unacceptably invariable, thus pointing to the need for new approaches centered in the molecular basis of the disease. Ewing sarcoma driving mutation, EWS–FLI1, which results from a chromosomal translocation, encodes an aberrant transcription factor. Since its first characterization in 1990s, many molecular targets have been described to be regulated by this chimeric transcription factor. Their contribution to orchestrate Ewing sarcoma phenotype has been reported over the last decades. In this work, we will focus on the description of a selection of EWS/FLI1 targets, their functional role, and their potential clinical relevance. We will also discuss their role in other types of cancer as well as the need for further studies to be performed in order to achieve a broader understanding of their particular contribution to Ewing sarcoma development.

• CCK
• DAX-1
• EWS/FLI1
• Ewing sarcoma
• FOXM1
• FOXO1
• GLI1
• LOX

• ETS
• Ewing sarcoma
• YK-4-279
• cell cycle
• chromatin
• drug screening
• epigenetics
• mesenchymal stem cells
• micro satellites
• neural crest stem cells
• pediatric oncology
• transcription factor

Homoharringtonine (HHT) is a kind of cephalotaxus alkaloid used in traditional Chinese medicine. Although HHT has been successfully used as a therapeutic agent for leukemia, the drug resistance and toxicity are major concerns. MicroRNAs (miRNAs) have been identified to modulate cellular sensitivity to anticancer drugs. We examined the synergistic action between miR-370 and HHT in vitro and in vivo.

The synergistic action between miR-370 and HHT was examined by flow cytometry. The effect of HHT on miR-370 expression was determined by quantitative RT-PCR (qRT-PCR). The expression of miR-370 and Forkhead box M1 (FoxM1) in 23 patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) and 10 patients with blast-crisis CML (CML-BP) as well as miR-370–targeted FoxM1 was determined by qRT-PCR and western blot analysis.

Ectopic expression of miR-370 sensitized the CML K562 cell line to HHT by targeting FoxM1, the major regulator in cell proliferation and apoptosis. miR-370 significantly promoted HHT-mediated cell apoptosis and miR-370 and HHT cooperated in affecting FoxM1 expression. As well, miR-370 was moderately upregulated after HHT treatment in K562 cells. In addition, the expression of miR-370 was significantly reduced in CML patients as compared with healthy controls. Furthermore, the expression of miR-370 was lower in CML-BP than CML-CP patients.

MiR-370 sensitized K562 cells to HHT by inducing apoptosis in part by downregulation of FoxM1 expression. These findings may provide further information for CML treatment with HHT.

The poor prognosis of Ewing’s sarcoma (EWS), together with its high lethal recurrence rate and the side-effects of current treatments, call for novel targeted therapies with greater curative effectiveness and substantially reduced side-effects. The oncogenic chimeric protein EWS/FLI1 is the key malignancy driver in most EWSs, regulating numerous target genes, many of which influence cell cycle progression. It has often been argued that targeting proteins regulated directly or indirectly by EWS/FLI1 may provide improved therapeutic options for EWS. In this context, our study examined FoxM1, a key cell cycle regulating transcription factor, reported to be expressed in EWS and influenced by EWS/FLI1. Thiostrepton, a naturally occurring small molecule, has been shown to selectively inhibit FoxM1 expression in cancer cells. We demonstrate that in EWS, in addition to inhibiting FoxM1 expression, thiostrepton downregulates the expression of EWS/FLI1, both at the mRNA and protein levels, leading to cell cycle arrest and, ultimately, to apoptotic cell death. We also show that thiostrepton treatment reduces the tumorigenicity of EWS cells, significantly delaying the growth of nude mouse xenograft tumors. Results from this study demonstrate a novel action of thiostrepton as inhibitor of the expression of the EWS/FLI1 oncoprotein in vitro and in vivo, and that it shows greater efficacy against EWS than against other tumor types, as it is active on EWS cells and tumors at concentrations lower than those reported to have effective inhibitory activity on tumor cells derived from other cancers. Owing to the dual action of this small molecule, our findings suggest that thiostrepton may be particularly effective as a novel agent for the treatment of EWS patients.