Role of FOXM1 and AURKB in regulating keratinocyte function in psoriasis.

Objective: This study investigated the effect of forkhead box M1 (FOXM1) and Aurora kinase B (AURKB) on the epidermal function of keratinocytes. Methods: Bioinformatics analysis was used to analyze the co-expression network of FOXM1 and its correlation with AURKB. The expression of FOXM1 and AURKB in tissues and cells was detected by immunofluorescence and real-time quantitative polymerase chain reaction, respectively. HaCaT cells were transfected with si-FOXM1 to knock down FOXM1. Cell proliferation was detected by cell counting kit-8 assay. Cell migration was detected by scratch assay. Cell invasion was detected by the Transwell invasion assay. Cell apoptosis and cell cycle were detected by flow cytometry. Results: FOXM1 and AURKB were positively correlated and highly expressed in psoriatic lesions. After transfection of si-FOXM1, the expression levels of FOXM1 and AURKB genes significantly decreased. The proliferation of HaCaT cells decreased, the apoptosis rate increased significantly, and the proportion of cells in the G1 phase increased significantly, while the proportion of cells in the S phase decreased significantly. The scratch closure of HaCaT cells was reduced, and the number of cell invasions decreased significantly. Conclusion: FOXM1 and AURKB may affect the progression of psoriasis by regulating the proliferation, cell cycle, migration, and invasion of keratinocytes.

Biochemical characterization of the feedforward loop between CDK1 and FOXM1 in epidermal stem cells.

The complex network governing self-renewal in epidermal stem cells (EPSCs) is only partially defined. FOXM1 is one of the main players in this network, but the upstream signals regulating its activity remain to be elucidated. In this study, we identify cyclin-dependent kinase 1 (CDK1) as the principal kinase controlling FOXM1 activity in human primary keratinocytes. Mass spectrometry identified CDK1 as a key hub in a stem cell-associated protein network, showing its upregulation and interaction with essential self renewal-related markers. CDK1 phosphorylates FOXM1 at specific residues, stabilizing the protein and enhancing its nuclear localization and transcriptional activity, promoting self-renewal. Additionally, FOXM1 binds to the CDK1 promoter, inducing its expression.We identify the CDK1-FOXM1 feedforward loop as a critical axis sustaining EPSCs during in vitro cultivation. Understanding the upstream regulators of FOXM1 activity offers new insights into the biochemical mechanisms underlying self-renewal and differentiation in human primary keratinocytes.

SIRT2 deacetylates and decreases the expression of FOXM1 in colon cancer.

New FOXM1-specific inhibitors with the potential to be used for therapeutic purposes are under extensive research. We hypothesized that deacetylation of FOXM1 would decrease protein expression, thus providing novel therapeutic management of colon cancers. Immunostaining was used to determine FOXM1 and SIRT2 expressions in human colon cancer tissue microarrays (n = 90) from Stage I to Stage IV. SIRT2-FOXM1 interaction was evaluated in colon cancer cells using immunoprecipitation. Deacetylation of FOXM1 via SIRT2 was determined using in vitro deacetylation assays. FOXM1 could be hyper-acetylated when p300 and pCAF histone acetyltransferases were administered alongside deacetylase inhibitors. We detected that SIRT2 and FOXM1 physically interacted, and SIRT2 deacetylated FOXM1 in vitro. SIRT2 overexpression led to a significant decrease while knockdown of SIRT2 increased the FOXM1 expression in HCT116 human colon carcinoma cells. In the analysis of 90 human colorectal cancer samples, high SIRT2 expression was observed in about 49% of colorectal cancer, intermediate in 29%, and low or no staining in 22%. Strong SIRT2 expression was found to be negatively associated with the FOXM1 staining in our clinical cohort. This study reveals a molecular interaction and association between SIRT2 and FOXM1 expression in colon cancer cell lines and human colon cancer samples, and suggests that targeting SIRT2 activity using small molecule modulators may be a promising therapeutic approach for colorectal cancer.

CLDN11 deficiency upregulates FOXM1 to facilitate breast tumor progression through hedgehog signaling pathway.

Claudins (CLDNs) play a crucial role in regulating the permeability of epithelial barriers and can impact tumor behavior through alterations in their expression. However, the precise mechanisms underlying the involvement of CLDNs in breast cancer progression remain unclear. This study aimed to investigate the role of CLDN11 in breast cancer progression. Utilizing the TCGA database and clinical specimens from breast cancer patients, we observed reduced expression of CLDN11 in tumor tissues, which correlated with poor prognosis in breast cancer patients. In vitro, silencing of CLDN11 enhanced the proliferative and migratory characteristics of breast cancer cell lines MCF-7 and MDA-MB-231. Mechanistically, CLDN11 deficiency promoted the upregulation of Forkhead Box M1 (FOXM1) by activating the hedgehog signaling pathway, thereby sustaining tumor progression in breast cancer. In vivo, blockade of hedgehog signaling suppressed the tumor progression induced by CLDN11 silencing. Our study highlights the significance of the CLDN11/FOXM1 axis in breast cancer progression, suggesting CLDN11 as a potential diagnostic indicator and therapeutic target for clinical therapy.

Asiaticoside protects against lung injury induced by intestinal ischemia/reperfusion via the upregulation of FoxM1.

Systemic inflammatory response syndrome and respiratory distress syndrome can be induced by lung injury caused by intestinal ischemia/reperfusion (II/R). There is no effective medical treatment for II/R-induced lung injury. Studies have shown that asiaticoside (AS) protects against lung injury and ischemia/reperfusion injury in several organs. We established a rat II/R damage model and collected lung tissue. Six groups (n = 10) were created: (1) the sham group; (2) the II/R group; (3) the II/R + AS (40) group; (4) the II/R + AS (80) group; (5) the II/R + TST group; and (6) the II/R + AS + TST group. To assess the degree of lung damage induced by II/R, we also evaluated HE staining, the wet/dry ratio, oxidative stress, inflammation and apoptosis in the lung tissues. Our results indicated that the severity of lung injury score, wet/dry ratio, oxidative stress, inflammatory factor expression and amount of apoptosis were greater in the II/R-induced lung injury group than in the sham group. Furthermore, when AS was administered, lung injury, oxidative stress, inflammation and amount of apoptosis in the lung tissues were obviously lower than those in the II/R group. Additionally, compared with that in the sham group, the expression of FoxM1 in the lung tissue in the II/R group was significantly greater, and FoxM1 expression in the lung tissue was significantly greater following AS administration. Compared with the AS alone, the administration of thiostrepton (a FoxM1 inhibitor) and AS exacerbated the lung damage induced by II/R. According to our research, AS prevents the lung damage induced by II/R by reducing oxidative stress, inflammation and apoptosis by activating FoxM1 expression.

FOXM1 derived from Triple negative breast cancer exosomes promotes cancer progression by activating IDO1 transcription in macrophages to suppress ferroptosis and induce M2 polarization of Tumor-associated macrophages.

To explore the oncogenic mechanism of FOXM1 in the tumor microenvironment (TME) regarding triple negative breast cancer (TNBC) promotion. The mRNA and protein levels of target genes in TNBC cells and their exosomes were detected by RT-qPCR and western blot. Co-culture models of TNBC cells and THP-1/M0 macrophages was established to detect the impact of co-culture on FOXM1 expression and macrophage polarization direction. The bioinformatics website was used to predict the binding sites between the FOXM1 and IDO1 promoter, which were further validated using dual-luciferase reporter assay and chromatin immunoprecipitation (ChIP) assay. Finally, after erastin-induced ferroptosis, Cell Counting Kit-8 (CCK-8), terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL), and other experiments were conducted to investigate whether the FOXM1/IDO1 axis regulates M2 macrophage polarization through ferroptosis. It was found that FOXM1 was highly expressed in exosomes derived from TNBC cells, and TNBC cells upregulated FOXM1 expression in THP-1 cells through exosomes to promote M2 macrophage polarization. Furthermore, FOXM1 upregulated IDO1 in M2-type TAMs by regulating transcription. Lastly, FOXM1/IDO1 inhibited ferroptosis, promoting M2 macrophage polarization, thereby advancing TNBC progression. In conclusions, FOXM1 derived from TNBC cell-derived exosomes activated IDO1 transcription in TAMs to inhibit ferroptosis, promoting TAMs' M2 polarization and exerting carcinogenic effects.

Fangchinoline inhibits metastasis and reduces inflammation-induced epithelial-mesenchymal transition by targeting the FOXM1-ADAM17 axis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. Efforts have been focused on developing new anti-HCC agents and understanding their pharmacology. However, few agents have been able to effectively combat tumor growth and invasiveness due to the rapid progression of HCC. In this study, we discovered that fangchinoline (FAN), a bisbenzylisoquinoline alkaloid derived from Stephania tetrandra S. Moore, effectively inhibited the migration, invasion, and epithelial-mesenchymal transition (EMT) of HCC cells. FAN treatment also led to the suppression of IL6 and IL1ß release, as well as the expression of inflammation-related proteins such as COX-2 and iNOS, and the activation of the NF-κB pathway, thereby reducing inflammation-related EMT. Additionally, FAN directly bound to forkhead box protein M1 (FOXM1), resulting in decreased levels of FOXM1 proteins and disruption of the FOXM1-ADAM17 axis. Our in vivo findings confirmed that FAN effectively hindered the growth and lung metastasis of HCCLM3-xenograft tumors. Importantly, the upregulation of FOXM1 in HCC tissue suggested that targeting FOXM1 inhibition with FAN or its inhibitors could be a promising therapeutic approach for HCC. Overall, this study elucidated the anti-tumor effects and potential pharmacological mechanisms of FAN, and proposed that targeting FOXM1 inhibition may be an effective therapeutic strategy for HCC with potential clinical applications.

The activation of asparagine synthetase by the transcription factor FOXM1 plays a pivotal role in the initiation and progression of ESCC.

This study explores the role of the transcription factor FOXM1 in the initiation and progression of oesophageal squamous cell carcinoma (ESCC). Our findings reveal that FOXM1 is highly expressed in ESCC and correlates with the prognosis of the disease. The relationship between FOXM1 and asparagine synthetase (ASNS) is investigated, and the study demonstrates that FOXM1 activates ASNS, impacting the tumour stemness of ESCC. In this study, we reveal the association between FOXM1 and ESCC development, as well as FOXM1's promotion of migration and proliferation in ESCC cells. The study also highlights FOXM1's regulation of ASNS transcription and the functional role of ASNS in ESCC metastasis and growth. Furthermore, the study explores the impact of FOXM1 and ASNS on ESCC stemness and their potential implications for chemotherapy resistance.

Exosomal miR-664a-5p as a therapeutic target biomarker for PARP inhibitor response in prostate cancer.

This study investigated the role of urinary exosomal miR-664a-5p as a potential therapeutic target in prostate cancer (PCa). Small RNA sequencing of urinary exosomes from PCa patients with different responses to PARP inhibitors revealed that miR-664a-5p was significantly upregulated in responsive patients. Overexpression of miR-664a-5p enhanced the sensitivity of PCa cells to PARP inhibitors by directly targeting FOXM1, a transcription factor involved in DNA damage repair, leading to the downregulation of DNA damage response genes. Combined treatment with miR-664a-5p and olaparib synergistically inhibited tumor growth in a PC-3 xenograft mouse model. These findings suggest that urinary exosomal miR-664a-5p is a potential therapeutic biomarker for PARP inhibitor response in PCa patients, and targeting FOXM1 via miR-664a-5p represents a promising strategy for enhancing PARP inhibitor efficacy in PCa treatment.

MicroRNA-532-3p Modulates Colorectal Cancer Cell Proliferation and Invasion via Suppression of FOXM1.

Colorectal cancer (CRC) is a heterogeneous disease and classified into various subtypes, among which transcriptional alterations result in CRC progression, metastasis, and drug resistance. Forkhead-box M1 (FOXM1) is a proliferation-associated transcription factor which is overexpressed in CRC and the mechanisms of FOXM1 regulation have been under investigation. Previously, we showed that FOXM1 binds to promoters of certain microRNAs. Database mining led to several microRNAs that might interact with FOXM1 3'UTR. The interactions between shortlisted microRNAs and FOXM1 3'UTR were quantitated by a dual-luciferase reporter assay. MicroRNA-532-3p interacted with the 3'UTR of the FOXM1 mRNA transcript most efficiently. MicroRNA-532-3p was ectopically overexpressed in colorectal cancer (CRC) cell lines, leading to reduced transcript and protein levels of FOXM1 and cyclin B1, a direct transcriptional target of FOXM1. Further, a clonogenic assay was conducted in overexpressed miR-532-3p CRC cells that revealed a decline in the ability of cells to form colonies and a reduction in migratory and invading potential. These alterations were reinforced at molecular levels by the altered transcript and protein levels of the conventional EMT markers E-cadherin and vimentin. Overall, this study identifies the regulation of FOXM1 by microRNA-532-3p via its interaction with FOXM1 3'UTR, resulting in the suppression of proliferation, migration, and invasion, suggesting its role as a tumor suppressor in CRC.

Casticin suppresses self-renewal related stemness via miR-342-3p-mediated FoxM1 downregulation in cervical cancer cells.

BACKGROUND: Casticin (CAS), a natural flavonoid found in Viticis Fructus, Viticis Cannabifoliae Fructus, and Semen Euphorbiae, shows anti-inflammatory activity and efficacy against various cancers. However, its effect on stemness associated with self-renewal in cervical cancer (CC) cells remains unclear, as well as the underlying mechanism. PURPOSE: The primary objective of this study was to examine the effect of CAS on CC stemness and to explore the underpinning regulatory mechanism. METHODS: HeLa cells underwent treatment with varying concentrations of CAS (0, 10, 30, 100 nM). To evaluate the impacts of CAS on CC stemness and tumorigenicity, sphere- and colony-formation assays and a xenograft model were employed. The study involved screening for changes in miRNAs and their target genes. The miRNA array identified an upregulation in miRNAs, whereas the mRNA array detected a downregulation of specific target genes. The latter genes were found to regulate stem cell-related genes through miR-342-3p in HeLa cells administered CAS. Next, whether miR-342-3p directly targets FOXM1 when upregulated by CAS was assessed by the luciferase reporter assay. qRT-PCR was performed to analyze miR-342-3p expression. Additionally, immunoblotting was conducted to assess the protein amounts of FoxM1 and stemness-related factors (CD133, CD49f, Nanog, and Sox2). Function rescue experiments were conducted to determine the mechanism of CAS in stemness regulation. These experiments involved utilizing a miR-342-3p inhibitor and overexpressing FOXM1 in HeLa cells. RESULTS: CAS decreased in vitro stemness, suppressing sphere- and colony-formation capabilities of CC. It also dose-dependently downregulated the expression of stemness-associated proteins, including CD133, CD49f, Nanog, and Sox2. Moreover, CAS inhibited in vivo carcinogenesis, remarkably reducing tumor growth in mice bearing HeLa cell xenografts. Analysis revealed downregulated FOXM1 expression in HeLa cells treated with CAS. In the luciferase reporter assay, miR-342-3p was found to directly target FOXM1 in CAS-treated HeLa cells. Additionally, miR-342-3p inhibitor transfection successfully rescued CAS' suppressive impact on stemness. Furthermore, overexpression of FOXM1 did not induce changes in miR-342-3p expression. However, it effectively rescued CAS' suppressive effects on stemness. Moreover, CAS also inhibited stemness, upregulated miR-342-3p, and lowered FOXM1 expression in the SiHa cell line. CONCLUSION: CAS suppresses self-renewal-associated stemness by targeting FOXM1 via miR-342-3p upregulation. These findings suggest CAS is promising as a novel therapeutic candidate in CC.

TGF-ß1 and FOXM1 siRNA co-loaded nanoparticles by disulfide crosslinked PEG-PDMAEMA for the treatment of triple-negative breast cancer and its bone metastases in vitro.

INTRODUCTION: Triple-negative breast cancer (TNBC) is characterized by higher malignancy and mortality and is prone to distant metastasis, among which bone is the most common site. It's urgent to explore new strategies for the treatment of TNBC and its bone metastases. METHODS: A tumor environment responsive vector, poly-(dimethylaminoethyl methacrylate)-SS-poly(ethylene glycol)-SS-poly-(dimethylaminoethyl methacrylate) (PDMAEMA-SS-PEG-SS-PDMAEMA), was constructed to co-delivery transforming growth factor-ß1 (TGF-ß1) siRNA and forkhead box M1 (FOXM1) siRNA in MDA-MB-231 cells. The preparation, characterization, in vitro release, stability, and transfection efficiency of nanoparticles were measured. Cell viability, migration, and invasion of MDA-MB-231 cells were determined. Cell chemotactic migration and cell heterogeneity adhesion of MDA-MB-231 cells to the human osteoblast-like cell line MG-63 were determined. RESULTS: PDMAEMA-SS-PEG-SS-PDMAEMA self-assembled with siRNA at N/P of 15:1 into nanoparticles with a particle size of 122 nm. In vitro release exhibited redox and pH sensitivity, and the nanoparticles protected siRNA from degradation by RNase and serum protein, remaining stable at 4 °C with similar transfection efficiency with lipo2000. Nanoparticles co-loaded with TGF-ß1 siRNA and FOXM1 siRNA inhibited the cell viability, migration and invasion of MDA-MB-231 cells, as well as chemotactic migration and heterogeneous adhesion of MDA-MB-231 cells to MG-63 cells, showing a synergetic effect. After gene silencing on TGF-ß1 and FOXM1, the epithelial to mesenchymal transition (EMT) related molecules vimentin mRNA expression decreased while E-cadherin increased. CONCLUSIONS: PDMAEMA-SS-PEG-SS-PDMAEMA was suitable for TGF-ß1 siRNA and FOXM1 siRNA delivery, exhibiting a synergetic inhibition effect on TNBC and its bone metastases, which might be related to its synergetic inhibition on EMT.

Linking FOXM1 and PD-L1 to CDK4/6-MEK targeted therapy resistance in malignant peripheral nerve sheath tumors.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive, Ras-driven sarcomas characterized by loss of the NF1 tumor suppressor gene and hyperactivation of MEK and CDK4/6 kinases. MPNSTs lack effective therapies. We recently demonstrated remarkable efficacy of dual CDK4/6-MEK inhibition in mice with de novo MPNSTs, which was heightened by combined targeting of the immune checkpoint protein, PD-L1. The triple combination therapy targeting CDK4/6, MEK, and PD-L1 led to extended MPNST regression and improved survival, although most tumors eventually acquired drug resistance. Here, we consider the immune activation phenotype caused by CDK4/6-MEK inhibition in MPNSTs that uniquely involved intratumoral plasma cell accumulation. We discuss how PD-L1 and FOXM1, a tumor-promoting transcription factor, are functionally linked and may be key mediators of resistance to CDK4/6-MEK targeted therapies. Finally, the role of FOXM1 in suppressing anti-tumor immunity and potentially thwarting immune-based therapies is considered. We suggest that future therapeutic strategies targeting the oncogenic network of CDK4/6, MEK, PD-L1, and FOXM1 represent exciting future treatment options for MPNST patients.

Senescent lung-resident mesenchymal stem cells drive pulmonary fibrogenesis through FGF-4/FOXM1 axis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an age-related disease featured with abnormal fibrotic response and compromised lung function. Cellular senescence is now considered as an essential driving mechanism for IPF. Given the poor knowledge of the mechanisms underpinning IPF progression, understanding the cellular processes and molecular pathways is critical for developing effective therapies of IPF. METHODS: Lung fibrosis was induced using bleomycin in C57BL/6 mice. Cellular senescence was measured by immunofluorescence. The effects of FGF-4 on fibroblast activation markers and signaling molecules were assessed with western blot and qPCR. RESULTS: We demonstrated elevated abundance of senescent mesenchymal stem cells (MSCs) in IPF lung tissues, which was tightly correlated with the severity of pulmonary fibrosis in vivo. In addition, senescent MSCs could effectively induce the phenotype of pulmonary fibrosis both in vitro and in vivo. To further confirm how senescent MSCs regulate IPF progression, we demonstrate that FGF-4 is significantly elevated in senescent MSCs, which can induce the activation of pulmonary fibroblasts. In vitro, FGF-4 can activate Wnt signaling in a FOXM1-dependent manner. Inhibition of FOXM1 via thiostrepton effectively impairs FGF-4-induced activation of pulmonary fibroblast and dramatically suppresses the development of pulmonary fibrosis. CONCLUSION: These findings reveal that FGF-4 plays a crucial role in senescent MSCs-mediated pulmonary fibrogenesis, and suggests that strategies aimed at deletion of senescent MSCs or blocking the FGF-4/FOXM1 axis could be effective in the therapy of IPF.

CD133+/ABCC5+ cervical cancer cells exhibit cancer stem cell properties.

Objective: This study explores the correlation between Forkhead box M1 (FOXM1) and ATP-binding cassette subfamily C member 5 (ABCC5) in relation to paclitaxel resistance in cervical cancer. It aims to identify potential cervical cancer stem cell markers, offering fresh perspectives for developing therapeutic strategies to overcome paclitaxel chemoresistance in cervical cancer. Methods: Paclitaxel-resistant Hela cells (Hela/Taxol) were developed by intermittently exposing Hela cells to progressively increasing concentrations of paclitaxel. We assessed the biological properties of both Hela and Hela/Taxol cells using various assays: cell proliferation, clonogenic, cell cycle, apoptosis, scratch, and transwell. To determine which markers better represent tumor stem cells, we analyzed various known and potential stem cell markers in combination. Flow cytometry was employed to measure the proportion of positive markers in both parental and drug-resistant cell lines. Following statistical analysis to establish relative stability, CD133+ABCC5+ cells were sorted for further examination. Subsequent tests included sphere-forming assays and Western blot analysis to detect the presence of the stem cell-specific protein Sox2, aiding in the identification of viable cervical cancer stem cell markers. Results: The Hela/Taxol cell line exhibited significantly enhanced proliferation, migration, and invasion capabilities compared to the Hela cell line, alongside a marked reduction in apoptosis rates (P < 0.01). Notably, proportions of CD44+, CD24+CD44+, ABCC5+, CD24+CD44+ABCC5+, CD44+ABCC5+, CD24+CD44+FOXM1+, CD44+FOXM1+, CD133+ABCC5+, and CD133+FOXM1+ were significantly higher (P < 0.05). Furthermore, the size and number of spheres formed byCD133+ABCC5+ cells were greater in the sorted Hela/Taxol line (P < 0.01), with increased expression of the stem cell marker Sox2 (P < 0.001). Conclusion: The Hela/Taxol cells demonstrate increased tumoral stemness, suggesting that CD133+ABCC5+ may serve as a novel marker for cervical cancer stem cells.

Rho GTPase activating protein 11A promotes tongue squamous cell carcinoma proliferation and is a transcriptional target of forkhead box M1.

Background/purpose: Rho GTPase activating protein 11A (ARHGAP11A) can facilitate GTP hydrolysis in RhoA. The functions of ARHGAP11A in oral squamous cell carcinoma (OSCC) have not yet been explored. This study aimed to investigate the expression profile of ARHGAP11A in OSCC, its correlation with patient prognosis, its effect on cell-cycle progression, and the mechanisms by which it is dysregulated. Materials and methods: Bioinformatics analysis was conducted using data from The Cancer Genome Atlas-Head and Neck Squamous Cell Carcinoma (TCGA-HNSC). Lentiviruses carrying ARHGAP11A shRNAs were employed to determine the effects of ARHGAP11A knockdown on tumor cell proliferation and cell-cycle progression. Dual-luciferase reporter assays were utilized to examine how FOXM1 transcriptionally regulates ARHGAP11A expression. Results: ARHGAP11A upregulation was associated with unfavorable overall survival (OS) in patients with TSCC (HR: 2.142, 95%CI: 1.224-3.749, P = 0.007), but not in patients with OSCC of sites other than the tongue. ARHGAP11A knockdown inhibited the proliferation of TSCC cells in vitro and in vivo, and induced G1 phase arrest. ARHGAP11A knockdown increased GTP-RhoA but decreased p-RB levels, while it did not affect the total expression of RhoA and RB. ARHGAP11A knockdown increased p27 and decreased cyclin E1 expression. ARHGAP11A is transcriptionally activated by FOXM1 via multiple FOXM1 binding sites in the promoter regions in TSCC cells. Conclusion: This study revealed the oncogenic role of ARHGAP11A in TSCC, highlighting its impact on cell-cycle control and tumor proliferation. Furthermore, the regulatory relationship between FOXM1 and ARHGAP11A provides new insights into the transcriptional networks in TSCC.

Cystathionine γ-Lyase Attenuates Vascular Smooth Muscle Cell Senescence via Foxm1-Gas1 Pathway to Mediate Arterial Stiffness.

Aims: Arterial stiffness, a hallmark of vascular aging, significantly contributes to hypertension and impaired organ perfusion. Vascular smooth muscle cell (VSMC) dysfunction, particularly VSMC senescence and its interaction with stiffness, is crucial in the pathogenesis of arterial stiffness. Although hydrogen sulfide (H2S) and its key enzyme cystathionine γ-lyase (CSE) are known to play roles in cardiovascular diseases, their effects on arterial stiffness are not well understood. Methods & Results: First, we observed a downregulation of CSE/H2S in the aortic media during biological aging and angiotensin II (AngII)-induced aging. The VSMC-specific CSE knockout mice were created by loxp-cre (Tagln-cre) system and which exacerbated AngII-induced aortic aging and stiffness in vivo and VSMC senescence and stiffness in vitro. Conversely, the CSE agonist norswertianolin mitigated these effects. Next, we identified growth arrest-specific 1 (Gas1) as a crucial target of CSE/H2S and found it to be a downstream target gene of forkhead box protein M1 (Foxm1). siRNA knockdown Foxm1 increased Gas1 transcription and reduced the protective effects of H2S on VSMC senescence and stiffness. Finally, we demonstrated that CSE/H2S sulfhydrates Foxm1 at the C210 site, regulating its nuclear translocation and activity, thus reducing VSMC senescence and stiffness. Innovation: Our findings highlight the protective role of CSE/H2S in arterial stiffness, emphasizing the novel contributions of CSE, Gas1, and Foxm1 to VSMC senescence and stiffness. Conclusion: Endogenous CSE/H2S in VSMCs reduces VSMC senescence and stiffness, thereby attenuating arterial stiffness and aging, partly through sulfhydration-mediated activation of Foxm1 and subsequent inhibition of Gas1 signaling pathways.

Deciphering the molecular landscape of the FAM72 gene family: Implications for stem cell biology and cancer.

Family with sequence similarity 72 (FAM72) is a protein-coding gene family located on chromosome 1 in humans, uniquely featuring four paralogs: FAM72A, FAM72B, FAM72C, and FAM72D. While FAM72's presence as a gene pair with the SLIT-ROBO Rho GTPase-activating protein 2 (SRGAP2) is intriguing, its functional roles, particularly in neural stem cells, remain incompletely understood. This review explores the distinct characteristics of FAM72, shedding light on its expression patterns, potential roles in cell cycle regulation, stem cell renewal and implications in neurogenesis and tumorigenesis.

Novel benzothiazole/benzothiazole thiazolidine-2,4-dione derivatives as potential FOXM1 inhibitors: In silico, synthesis, and in vitro studies.

The oncogenic transcription factor FOXM1 overexpressed in breast and other solid cancers, is a key driver of tumor growth and progression through complex interactions, making it an attractive molecular target for the development of targeted therapies. Despite the availability of small-molecule inhibitors, their limited specificity, potency, and efficacy hinder clinical translation. To identify effective FOXM1 inhibitors, we synthesized novel benzothiazole derivatives (KC10-KC13) and benzothiazole hybrids with thiazolidine-2,4-dione (KC21-KC36). These compounds were evaluated for FOXM1 inhibition. Molecular docking and molecular dynamics simulation analysis revealed their binding patterns and affinities for the FOXM1-DNA binding domain. The interactions with key amino acids such as Asn283, His287, and Arg286, crucial for FOXM1 inhibition, have been determined with the synthesized compounds. Additionally, the molecular modeling study indicated that KC12, KC21, and KC30 aligned structurally and interacted similarly to the reference compound FDI-6. In vitro studies with the MDA-MB-231 breast cancer cell line demonstrated that KC12, KC21, and KC30 significantly inhibited FOXM1, showing greater potency than FDI-6, with IC50 values of 6.13, 10.77, and 12.86 µM, respectively, versus 20.79 µM for FDI-6. Our findings suggest that KC12, KC21, and KC30 exhibit strong activity as FOXM1 inhibitors and may be suitable for in vivo animal studies.

FOXM1 Transcriptionally Co-Upregulates Centrosome Amplification and Clustering Genes and Is a Biomarker for Poor Prognosis in Androgen Receptor-Low Triple-Negative Breast Cancer.

There are currently no approved targeted treatments for quadruple-negative breast cancer [QNBC; ER-/PR-/HER2-/androgen receptor (AR)-], a subtype of triple-negative breast cancer (TNBC). AR-low TNBC is more proliferative and clinically aggressive than AR-high TNBC. Centrosome amplification (CA), a cancer hallmark, is rampant in TNBC, where it induces spindle multipolarity-mediated cell death unless centrosome clustering pathways are co-upregulated to avert these sequelae. We recently showed that genes that confer CA and centrosome clustering are strongly overexpressed in AR-low TNBCs relative to AR-high TNBCs. However, the molecular mechanisms that index centrosome clustering to the levels of CA are undefined. We argue that FOXM1, a cell cycle-regulated oncogene, links the expression of genes that drive CA to the expression of genes that act at kinetochores and along microtubules to facilitate centrosome clustering. We provide compelling evidence that upregulation of the FOXM1-E2F1-ATAD2 oncogene triad in AR-low TNBC is accompanied by CA and the co-upregulation of centrosome clustering proteins such as KIFC1, AURKB, BIRC5, and CDCA8, conferring profound dysregulation of cell cycle controls. Targeting FOXM1 in AR-low TNBC may render cancer cells incapable of clustering their centrosomes and impair their ability to generate excess centrosomes. Hence, our review illuminates FOXM1 as a potential actionable target for AR-low TNBC.