Foxm1 functions as an oncogene in multiple human malignancies, including cervical cancer. However, the potential of Foxm1 in the tumor microenvironment (TME) is still unknown. The purpose of the present study is to investigate the role of Foxm1 in CD8+ T cell anti-tumor immunity. RT-qPCR is conducted to calculate mRNA levels. JASPAR is used to predict the binding sites between Foxm1 and NLRP3. ChIP assay is performed to verify the occupancy of Foxm1 on the promoter of NLRP3. Modulatory relationship between Foxm1 and NLRP3 is verified by luciferase assay. In vivo assays are conducted to further verify the role of Foxm1/NLRP3 axis in cervical cancer. HE staining assay is applied for histological analysis. Flow cytometry is conducted to determine the functions of immune cells. We found that Foxm1 knockdown decreases tumor burden and suppresses tumor growth of cervical cancer. Foxm1 knock-down promotes the infiltration of CD8+ T cells. Foxm1 deficiency inhibits the exhaustion of CD8+ T cells and facilitates the maintenance of CD8+ effector and stem-like T cells. Moreover, Foxm1 transcriptionally inactivates NLRP3 and suppresses the expression of innate cytokines IL-1β and IL-18. However, inhibition of NLRP3 inflammasome or neutralizing IL-1β and IL-18 inhibits anti-tumor immunity and promoted tumor growth in Foxm1 deficiency in CD8+ T cells. In summary, targeting Foxm1 mediates the activation of NLRP3 inflammasome and stimulates CD8+ T cell anti-tumor immunity in cervical cancer.

Fertilization capacity and embryo survival rate are decreased in postovulatory aging oocytes, which results in a reduced reproductive rate in female animals. However, the key regulatory genes and related regulatory mechanisms involved in the process of postovulatory aging in oocytes remain unclear. In this study, RNA-Seq revealed that 3237 genes were differentially expressed in porcine oocytes between the MII and aging stages (MII + 24 h). The expression level of FOXM1 was increased at the aging stage, and FOXM1 was also observed to be enriched in many key biological processes, such as cell senescence, response to oxidative stress, and transcription, during porcine oocyte aging. Previous studies have shown that FOXM1 is involved in the regulation of various biological processes, such as oxidative stress, DNA damage repair, mitochondrial function, and cellular senescence, which suggests that FOXM1 may play a crucial role in the process of postovulatory aging. Therefore, in this study, we investigated the effects and mechanisms of FOXM1 on oxidative stress, mitochondrial function, DNA damage, and apoptosis during oocyte aging. Our study revealed that aging oocytes exhibited significantly increased ROS levels and significantly decreased GSH, SOD, T-AOC, and CAT levels than did oocytes at the MII stage and that FOXM1 inhibition exacerbated the changes in these levels in aging oocytes. In addition, FOXM1 inhibition increased the levels of DNA damage, apoptosis, and cell senescence in aging oocytes. A p21 inhibitor alleviated the effects of FOXM1 inhibition on oxidative stress, mitochondrial function, and DNA damage and thus alleviated the degree of senescence in aging oocytes. These results indicate that FOXM1 plays a crucial role in porcine oocyte aging. This study contributes to the understanding of the function and mechanism of FOXM1 during porcine oocyte aging and provides a theoretical basis for preventing oocyte aging and optimizing conditions for the in vitro culture of oocytes.

OBJECTIVE: Multiple myeloma (MM) is a deadly plasma cell malignancy with elusive pathogenesis. N6-methyladenosine (m6A) is critically engaged in hematological malignancies. The function of KIAA1429, the largest component of methyltransferases, is unknown. This study delved into the mechanism of KIAA1429 in MM, hoping to offer novel targets for MM therapy.
METHODS: Bone marrow samples were attained from 55 MM patients and 15 controls. KIAA1429, YTHDF1, and FOXM1 mRNA levels were detected and their correlation was analyzed. Cell viability, proliferation, cell cycle, and apoptosis were testified. Glycolysis-enhancing genes (HK2, ENO1, and LDHA), lactate production, and glucose uptake were evaluated. The interaction between FOXM1 mRNA and YTHDF1, m6A-modified FOXM1 level, and FOXM1 stability were assayed. A transplantation tumor model was built to confirm the mechanism of KIAA1429.
RESULTS: KIAA1429 was at high levels in MM patients and MM cells and linked to poor prognoses. KIAA1429 knockdown restrained MM cell viability, and proliferation, arrested G0/G1 phase, and increased apoptosis. KIAA1429 mRNA in plasma cells from MM patients was positively linked with to glycolysis-enhancing genes. The levels of glycolysis-enhancing genes, glucose uptake, and lactate production were repressed after KIAA1429 knockdown, along with reduced FOXM1 levels and stability. YTHDF1 recognized KIAA1429-methylated FOXM1 mRNA and raised FOXM1 stability. Knockdown of YTHDF1 curbed aerobic glycolysis and malignant behaviors in MM cells, which was nullified by FOXM1 overexpression. KIAA1429 knockdown also inhibited tumor growth in animal experiments.
CONCLUSIONS: KIAA1429 knockdown reduces FOXM1 expression through YTHDF1-mediated m6A modification, thus inhibiting MM aerobic glycolysis and tumorigenesis.

This study aims to investigate the hypothesis that Yes-associated protein (YAP) significantly regulates antioxidant potential and anti-apoptosis in UVB-induced cataract by exploring the underlying molecular mechanisms. To investigate the association between YAP and cataract, various experimental techniques were employed, including cell viability assessment, Annexin V FITC/PI assay, measurement of ROS production, RT-PCR, Western blot assay, and Immunoprecipitation. UVB exposure on human lens epithelium cells (HLECs) reduced total and nuclear YAP protein expression, increased cleaved/pro-caspase 3 ratios, decreased cell viability, and elevated ROS levels compared to controls. Similar Western blot results were observed in in vivo experiments involving UVB-treated mice. YAP knockdown in vitro demonstrated a decrease in the protein expression of FOXM1, Nrf2, and HO-1, which correlated with the mRNA expression, accompanied by an increase in cell apoptosis, caspase 3 activation, and the release of ROS. Conversely, YAP overexpression mitigated these effects induced by UVB irradiation. Immunoprecipitation revealed a FOXM1-YAP interaction. Notably, inhibiting FOXM1 decreased Nrf2 and HO-1, activating caspase 3. Additionally, administering the ROS inhibitor N-acetyl-L-cysteine (NAC) effectively mitigated the apoptotic effects induced by oxidative stress from UVB irradiation, rescuing the protein expression levels of YAP, FOXM1, Nrf2, and HO-1. The initial findings of our study demonstrate the existence of a feedback loop involving YAP, FOXM1, Nrf2, and ROS that significantly influences the cell apoptosis in HLECs under UVB-induced oxidative stress.

BACKGROUND: Long noncoding RNAs (lncRNAs) play vital regulatory functions in non-small cell lung cancer (NSCLC). Cisplatin (DDP) resistance has significantly decreased the effectiveness of DDP-based chemotherapy in NSCLC patients. This study aimed to investigate the effects of SH3PXD2A antisense RNA 1 (SH3PXD2A-AS1) on DDP resistance in NSCLC.
METHODS: Proliferation and apoptosis of DDP-resistant NSCLC cells were detected using cell counting kit-8 and flow cytometry assays. The interaction between SH3PXD2A-AS1 and sirtuin 7 (SIRT7) was assessed using co-immunoprecipitation (Co-IP), RNA pull-down, RNA immunoprecipitation (RIP), RNA fluorescence in situ hybridization, and immunofluorescence assays, while succinylation (SUCC) of Forkhead Box M1 (FOXM1) was analyzed by IP and Western blot assays. The role of SH3PXD2A-AS1 in vivo was explored using a xenografted tumor model.
RESULTS: Expression of SH3PXD2A-AS1 was found elevated in DDP-resistant NSCLC cells, while it\'s knocking down translated into suppression of cell viability and promotion of apoptosis. Moreover, silencing of SH3PXD2A-AS1 resulted in decreased FOXM1 protein level and enhanced FOXM1-SUCC protein level. The SIRT7 was found to interact with FOXM1, translating into inhibition of FOXM1 SUCC at the K259 site in human embryonic kidney (HEK)-293T cells. Overexpressing of SIRT7 reversed the increase of FOXM1-SUCC protein level and apoptosis, and the decrease of cell viability induced by silencing of SH3PXD2A-AS1. In tumor-bearing mice, SH3PXD2A-AS1 inhibition suppressed tumor growth and the protein levels of Ki67, SIRT7, and FOXM1.
CONCLUSIONS: SH3PXD2A-AS1 promoted DDP resistance in NSCLC cells by regulating FOXM1 SUCC via SIRT7, offering a promising therapeutic approach for NSCLC.

BACKGROUND: Breast cancer is one of the most common malignant tumors in women. Cell division cycle associated 5 (CDCA5), a master regulator of sister chromatid cohesion, was reported to be upregulated in several types of cancer. Here, the function and regulation mechanism of CDCA5 in breast cancer were explored.
METHODS: CDCA5 expression was identified through immunohistochemistry staining in breast cancer specimens. The correlation between CDCA5 expression with clinicopathological features and prognosis of breast cancer patients was analyzed using a tissue microarray. CDCA5 function in breast cancer was explored in CDCA5-overexpressed/knockdown cells and mice models. Co-IP, ChIP and dual-luciferase reporter assay assays were performed to clarify underlying molecular mechanisms.
RESULTS: We found that CDCA5 was expressed at a higher level in breast cancer tissues and cell lines, and overexpression of CDCA5 was significantly associated with poor prognosis of patients with breast cancer. Moreover, CDCA5 knockdown significantly suppressed the proliferation and migration, while promoted apoptosis in vitro. Mechanistically, we revealed that CDCA5 played an important role in promoting the binding of E2F transcription factor 1 (E2F1) to the forkhead box M1 (FOXM1) promoter. Furthermore, the data of in vitro and in vivo revealed that depletion of FOXM1 alleviated the effect of CDCA5 overexpression on breast cancer. Additionally, we revealed that the Wnt/β-catenin signaling pathway was required for CDCA5 induced progression of breast cancer.
CONCLUSIONS: We suggested that CDCA5 promoted progression of breast cancer via CDCA5/FOXM1/Wnt axis, CDCA5 might serve as a novel therapeutic target for breast cancer treatment.

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Unilateral moyamoya disease (MMD) represents a distinct subtype characterised by occlusive changes in the circle of Willis and abnormal vascular network formation. However, the aetiology and pathogenesis of unilateral MMD remain unclear. In this study, genetic screening of a family with unilateral MMD using whole-genome sequencing helped identify the c.1205 C > A variant of FOXM1, which encodes the transcription factor FOXM1 and plays a crucial role in angiogenesis and cell proliferation, as a susceptibility gene mutation. We demonstrated that this mutation significantly attenuated the proangiogenic effects of FOXM1 in human brain endothelial cells, leading to reduced proliferation, migration, and tube formation. Furthermore, FOXM1 c.1205 C > A results in increased apoptosis of human brain endothelial cells, mediated by the downregulation of the transcription of the apoptosis-inhibiting protein BCL2. These results suggest a potential role for the FOXM1 c.1205 C > A mutation in the pathogenesis of unilateral MMD and may contribute to the understanding and treatment of this condition.

BACKGROUND: Lung adenocarcinoma (LUAD) is the most common malignant tumor in respiratory system. Methyltransferase-like 1 (METTL1) is a driver of m7G modification in mRNA. This study aimed to demonstrate the role of METTL1 in the proliferation, invasion and Gefitinib-resistance of LUAD.
METHODS: Public datasets were downloaded from the Gene Expression Profiling Interactive Analysis (GEPIA) and GSE31210 datasets. Malignant tumor phenotypes were tested in vitro and in vivo through biological function assays and nude mouse with xenograft tumors. RNA immunoprecipitation assays were conducted to determine the interaction between METTL1 protein and FOXM1 mRNA. Public transcriptional database, Chromatin immunoprecipitation and luciferase report assays were conducted to detect the downstream target of a transcriptional factor FOXM1. Half maximal inhibitory concentration (IC50) was calculated to evaluate the sensitivity to Gefitinib in LUAD cells.
RESULTS: The results showed that METTL1 was upregulated in LUAD, and the high expression of METTL1 was associated with unfavorable prognosis. Through the m7G-dependent manner, METTL1 improved the RNA stability of FOXM1, leading to the up-regulation of FOXM1. FOXM1 transcriptionally suppressed PTPN13 expression. The METTL1/FOXM1/PTPN13 axis reduced the sensitivity of LUAD cells to Gefitinib. Taken together, our data suggested that METTL1 plays oncogenic role in LUAD through inducing the m7G modification of FOXM1, therefore METTL1 probably is a new potential therapeutic target to counteract Gefitinib resistance in LUAD.

Metabolic reprogramming is recognized as a hallmark of cancer, enabling cancer cells to acquire essential biomolecules for cell growth, often characterized by upregulated glycolysis and/or fatty acid synthesis-related genes. The transcription factor forkhead box M1 (FOXM1) has been implicated in various cancers, contributing significantly to their development, including colorectal cancer (CRC), a major global health concern. Despite FOXM1\'s established role in cancer, its specific involvement in the Warburg effect and fatty acid biosynthesis in CRC remains unclear. We analyzed The Cancer Genome Atlas (TCGA) Colonic Adenocarcinoma and Rectal Adenocarcinoma (COADREAD) datasets to derive the correlation of the expression levels between FOXM1 and multiple genes and the survival prognosis based on FOXM1 expression. Using two human CRC cell lines, HT29 and HCT116, we conducted RNAi or plasmid transfection procedures, followed by a series of assays, including RNA extraction, quantitative real-time polymerase chain reaction, Western blot analysis, cell metabolic assay, glucose uptake assay, Oil Red O staining, cell viability assay, and immunofluorescence analysis. Higher expression levels of FOXM1 correlated with a poorer survival prognosis, and the expression of FOXM1 was positively correlated with glycolysis-related genes SLC2A1 and LDHA, de novo lipogenesis-related genes ACACA and FASN, and MYC. FOXM1 appeared to modulate AKT/mammalian target of rapamycin (mTOR) signaling, the expression of c-Myc, proteins related to glycolysis and fatty acid biosynthesis, and glucose uptake, as well as extracellular acidification rate in HT29 and HCT116 cells. In summary, FOXM1 plays a regulatory role in glycolysis, fatty acid biosynthesis, and cellular energy consumption, thereby influencing CRC cell growth and patient prognosis.NEW & NOTEWORTHY Transcription factor forkhead box M1 (FOXM1) regulates glycolysis, fatty acid biosynthesis, and cellular energy consumption, which, together, controls cell growth and patient prognosis in colorectal cancer (CRC).