Subarachnoid hemorrhage (SAH) is a serious and common disease and accounts for about 10 % of acute stroke cases. BRCA-associated protein 1 (BAP1) belongs to the ubiquitin C-terminal hydrolases (UCHs) family, which plays an important role in cell metabolism and cell death, but its role in early brain injury (EBI) after SAH requires further study. Forkhead box protein O3a (FOXO3a) is a transcription factor involved in the regulation of cellular function and survival in the nervous system, including the oxidative stress response and neuronal death. This study aimed to explore the effect of FOXO3a and BAP1 on neuronal ferroptosis in the pathogenesis of EBI after SAH. In this study, the overexpression of BAP1 significantly inhibited GPX4 expression and exacerbated the degree of lipid peroxidation and ferroptosis in neurons after SAH. BAP1 regulated the transcription level of the SLC7A11 promoter by H2Aub. FOXO3a could transcriptionally regulate BAP1 to influence the levels of SLC7A11 and GPX4, and mediate lipid peroxidation and neuronal ferroptosis after SAH. Silencing FOXO3 and BAP1 significantly improved neurological deficit and cerebral edema, and reduced oxidative stress damage in SAH mice. After SAH, BAP1 could directly bind to the FKH-DBD + NLS domain located in FOXO3a protein through the UCH domain, and mediates deubiquitination of FOXO3a protein by the K48 site to maintain the stability of FOXO3a. Our findings elucidate the impact of FOXO3a and BAP1 on SLC7A11-related ferroptosis following SAH both in vivo and in vitro, and the inhibition of the FOXO3a-BAP1 axis can significantly attenuate neuronal damage and ferroptosis in EBI after SAH.

Globally, breast cancer is the most common cancer to affect women. There are different molecular and pathological factors that are involved in the uncontrolled proliferation of breast cancer cells. FOXN3 that is member of Forkhead box family proteins is well recognized for having a crucial role in different biological processes and is reported to be dysregulated in various malignancies. The studies to evaluate the significance of the FOXN3 gene in progression of breast cancer are still under progress. We in the current study aim to examine the FOXN3 gene expression in Indian breast cancer patients and find its clinical relevance. FOXN3 expression analysis using RT-PCR, immunohistochemistry, and western blotting was performed in tumor and normal tissue collected from 142 sporadic breast cancer patients. To identify the genetic aberrations in FOXN3 gene automated DNA sequencing was done. FOXN3 expression study revealed the elevated expression of FOXN3 mRNA in 61.26% of the cases whereas FOXN3 protein was seen to be overexpressed in 59.15% cases. Further, it was found that the elevated expression of FOXN3 mRNA was significantly correlated with the post-menopausal (p = 0.003) status and positive lymph node status (p = 0.049) of the patients. The FOXN3 protein expression also exhibited the significant association with menopausal status (p = 0.008), lymph node status (p = 0.001) and clinical stage (p = 0.018) of the patients. However, we did not find any mutation in the DNA binding domain of the FOXN3 gene in the Indian breast cancer cases. Our findings indicates that overexpression of FOXN3 gene in Indian breast cancer cases can have a potential role in breast cancer progression especially in advanced clinical stages.

Epithelial-mesenchymal transition (EMT) promotes several cancers by increasing tumor cell motility, disrupting epithelial cell phenotypes, apical-basal polarity, and intracellular connections, and enhancing tumor resistance to immunotherapy and chemotherapy. Mesenchymal-epithelial transition (MET), the opposite of EMT, causes tumor metastasis. EMT drives primary tumor cells, whereas MET inhibits them. Importantly, the complex network of EMT includes cell-cell interactions in the tumor microenvironment. Transcription factors, post-translational regulation, cytokine-mediated signaling, and microRNAs control EMT. In this review, we discussed how molecular mechanisms, signaling networks, and epithelial/mesenchymal states affect cancer treatment resistance and the tumor microenvironment. Research on immunotherapy and chemotherapy problems associated with EMT suggests that targeting EMT might be a potential cancer treatment resistance strategy.

Breast cancer remains one of the leading causes of mortality worldwide. While advancements in chemotherapy, immunotherapy, radiotherapy, and targeted therapies have significantly improved breast cancer treatment, many patients are diagnosed at advanced stages, where tumor cells exhibit aggressive behavior and therapy resistance. Understanding the mechanisms driving breast cancer progression is therefore critical. Metastasis is a major factor that drastically reduces patient prognosis and survival, accounting for most breast cancer-related deaths. ZEB proteins have emerged as key regulators of cancer metastasis. Beyond their role in metastasis, ZEB proteins also influence drug resistance. This review focuses on the role of ZEB1 and ZEB2 in regulating breast cancer metastasis. These proteins interact with components of the tumor microenvironment (TME) to drive cancer progression and metastasis. Additionally, ZEB proteins regulate angiogenesis through interactions with VEGF. Targeting ZEB proteins offers potential therapeutic benefits, particularly for aggressive breast cancer subtypes such as triple-negative breast cancer (TNBC), which often show poor therapeutic response. ZEB proteins also influence the sensitivity of breast cancer cells to chemotherapy, making them promising targets for enhancing treatment efficacy. Given their upregulation in breast cancer, ZEB proteins can serve as valuable diagnostic and prognostic markers.

Forkhead box O (FOXO) proteins are transcription factors that are involved in many physiological processes, including diabetes mellitus, which is a complex, multifactorial metabolic disorder. FOXO proteins are emerging as pivotal regulators in the progression of diabetes mellitus, mainly by inhibiting insulin or insulin-like growth factor, but little is known about their roles in diabetes mellitus. Although no targeted therapy exists to slow the development of diabetes and diabetes-related complications, several recent advances have clarified the molecular mechanisms underlying the disease. This review summarizes findings about FOXO proteins and diabetes mellitus, and sheds new light on the roles of FOXO proteins in diabetes mellitus.

Orthodontic treatment is widely applied for addressing orofacial skeletal deformities, with the remodeling of the alveolar bone under mechanical force being the key factor. FAK is essential for cellular response to mechanical force. However, the function of circFak has never been reported. In this study, the microarrays showed that circFak may affect osteogenesis under mechanical force. We aimed to verify the effect of circFak in force-related bone remodeling and investigate the underlying mechanisms.

Arraystar microarrays were used to identify differentially expressed circRNAs and microRNAs in response to mechanical stress. The subcellular distribution of circFak was analyzed via RT‒qPCR and FISH. ALP and ARS staining assays were performed to investigate the effects of circFak on osteogenesis. RNA sequencing, bioinformatics analysis, dual-luciferase reporter assays, and RNA immunoprecipitation were accomplished to discover the molecular mechanisms of circFak. AAV-sh-circFak mouse models with tooth movements were established. The role of circFak under mechanical force in vivo was assessed via immunofluorescence and micro-CT analyses.

CircFak expression was significantly upregulated under mechanical force. Osteogenic capacity of osteoblasts was positively correlated with the level of circFak. CircFak promoted mechanical force-induced osteogenesis through miR-425-5p/Ccn3 pathway, and further stimulated the phosphorylation of its parental sourced protein FAK. Our murine models showed that AAV-mediated circFak silencing suppressed osteogenesis.

CircFak could obviously promote osteogenesis under mechanical force and may possess ability to become a novel biomarker for prognosis of orthodontic treatments.

FOXO3a is a transcription factor involved in cell growth inhibition and apoptosis. FOXO3a is localized in the cytoplasm in cancer cells, and its nuclear translocation by small molecules is expected to prevent cancer cell growth. In this study, we screened a fungal broth library in HeLa cells using fluorescently labeled FOXO3a and an AI-based imaging system. We identified violaceoid F, which translocates FOXO3a into the nucleus by inhibiting CRM1, which is responsible for nuclear protein export. Violaceoid F was observed to target the reactive cysteine of CRM1 through its α, β-epoxyketone. However, because violaceoid F did not inhibit Crm1 in fission yeast cells, it seems to target cysteine residue(s) other than Cys528 of human CRM1 which are not targeted by other known CRM1 inhibitors, indicating that violaceoid F inhibits CRM1 via a novel mechanism.

We investigated the involvement of FOXO3a in lipopolysaccharide (LPS)-induced inflammation in primary human dental pulp cells (HDPCs).

HDPCs that were isolated from donors undergoing tooth extraction for orthodontic purposes were cultured with or without 1 μg/mL LPS at various intervals. The FOXO3a localization in the HDPCs was verified using immunofluorescence. Proinflammatory cytokines, such as interleukin (IL) 1β, IL6, and IL8, as well as their underlying mechanisms were assessed by observing gene and protein expressions through quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analyses.

LPS treatment enhanced the expressions of IL1β, IL6, and IL8 in HDPCs, concurrently activating nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Furthermore, FOXO3a expression was higher in the LPS-stimulated HDPCs, as confirmed by immunofluorescence localization. The results of loss-/gain-of-function approaches confirmed the regulatory role of FOXO3a in inflammatory HDPCs. FOXO3a knockdown attenuated proinflammatory cytokine expression; FOXO3a overexpression augmented their expression levels. FOXO3a inhibited retinoic acid receptor-related orphan receptor alpha (RORα) expression, thereby inactivating NFκB.

Our findings suggest that FOXO3a contributes to homeostasis in HDPCs through modulating the expression of proinflammatory cytokines under inflammatory conditions.

Therapy resistance, including castration-resistance and metastasis, remains a major hurdle in the treatment of prostate cancer. In order to identify novel therapeutic targets and treatment modalities for prostate cancer, we conducted a comprehensive literature search on PubMed to identify de-regulated circular RNAs that influence treatment efficacy in preclinical prostate cancer-related in vivo models. Our analysis identified 49 circular RNAs associated with various processes, including treatment resistance, transmembrane and secreted proteins, transcription factors, signaling cascades, human antigen R, nuclear receptor binding, ubiquitination, metabolism, epigenetics and other target categories. The identified targets and circular RNAs can be further scrutinized through target validation approaches. Down-regulated circular RNAs are candidates for reconstitution therapy, while up-regulated RNAs can be inhibited using small interfering RNA (siRNA), antisense oligonucleotides (ASO) or clustered regularly interspaced short palindromic repeats/CRISPR associated (CRISPR-CAS)-related approaches.

Forkhead box (FOX) genes are a family of transcription factors that participate in many biological activities, from early embryogenesis to the formation of organs, and from regulation of glucose metabolism to regulation of longevity. Given the extensive influence in the multicellular process, FOX family proteins are responsible for the progression of many types of cancers, especially lung cancer, breast cancer, prostate cancer, and other cancers. Breast cancer is the most common cancer among women, and 2.3 million women were diagnosed in 2020. So, various drugs targeting the FOX signaling pathway have been developed to inhibit breast cancer progression. While the role of the FOX family gene in cancer development has not received enough attention, discovering more potential drugs targeting the FOX signaling pathway is urgently demanded. Here, we review the main members in the FOX gene family and summarize their signaling pathway, including the regulation of the FOX genes and their effects on breast cancer progression. We hope this review will emphasize the understanding of the role of the FOX gene in breast cancer and inspire the discovery of effective anti-breast cancer medicines targeting the FOX gene in the future.

Ovarian cancer is the seventh most common lethal tumor among women in the world. FOXM1 is a transcription factor implicated in the initiation and progression of ovarian cancer by regulating key oncogenic genes. The role of regulatory regions in regulating the expression of FOXM1 in ovarian cancer is not completely clarified. Treatment with bromodomain and extraterminal (BET) inhibitors JQ-1 and I-BET were explored in ovarian cancer cell lines (OVCAR3, A2780, or SKOV3) to evaluate FOXM1 expression and biological behavior by qPCR, CCK8 assay, colony formation assay, wound-healing, and transwell assays. The regulatory regions (enhancer sequence spanning promoter or exon 1) of FOXM1 were deleted using CRISPR-Cas9 in the OVCAR3 cell line. FOXM1 expression and tumor biological behavior were further assessed in FOXM1 regulatory regions deleted OVCAR3 cell line. The mouse xenograft model was assessed at the indicated time points following subcutaneous injection of enhancer-deleted cells. Treatment with the JQ-1 and I-BET reduced the expression of FOXM1, decreasing cell proliferation, migration, and invasion in a panel of ovarian cancer cell lines including OVCAR3, A2780, and SKOV3 cells. By mining the published ChIP-sequencing data (H3K27Ac) from 12 ovarian cancer cell lines, we identified a potential enhancer and promoter region. Deletion of the spanning enhancer and promoter region of FOXM1 reduced mRNA and protein expression. Similarly, cell proliferation, migration, invasion, and tumorigenesis in both cells and mouse xenograft models were significantly attenuated. Our study demonstrates that JQ-1 and I-BET can regulate the expression of the FOXM1 gene-relating network. These data also indicate that disruption of the span enhancer and promoter region activity of FOXM1 has a vital role in the anti-ovarian cancer effect, hiding a potential opportunity for the evaluation of this non-coding DNA deletion disrupts the FOXM1 transcriptional network in ovarian cancer development.

The human FOXM1 transcription factor controls cell cycle progression and genome stability, and it has been correlated to the onset and progression of many tumor types.

In our study, we collected all recent sequence and quantitative transcriptomics data about FOXM1, testing its presence across vertebrate evolution and its upregulation in cancer, both in bulk tissue contexts (by comparing the TCGA tumor dataset and the GTEx normal tissue dataset) and in single-cell contexts.

FOXM1 is significantly and consistently upregulated in all tested tumor types, as well as in tumor cells within a cancer microenvironment. Its upregulation reverberates in the upregulation of its target genes and can be used as a biomarker for poor cancer outcome in at least four tumor types.

Despite its lack of cancer-related mutations and amplifications, the recurring upregulation of FOXM1 in all tumors puts a focusing lens on this gene as a candidate pan-cancer master regulator.

Treatment of advanced prostate cancer is challenging due to a lack of effective therapies. Therefore, it is important to understand the molecular mechanisms underlying therapeutic resistance in prostate cancer and to identify promising drug targets offering significant clinical advantages. Given the pivotal role of dysregulated transcriptional programs in the therapeutic response, it is essential to prioritize translational efforts targeting cancer-associated transcription factors (TFs). The present study investigated whether chromatin accessibility was associated with therapeutic resistance in prostate cancer using Assay for Transposase-Accessible Chromatin with sequencing (ATAC-seq) data. The bioinformatics analysis identified differences in chromatin accessibility between the drug response (Remission) and drug resistance (Disease) groups. Additionally, a significant association was observed between chromatin accessibility, transcriptional output and TF activity. Among TFs, forkhead box protein M1 (FOXM1) was identified as a TF with high activity and expression in the Disease group. Notably, the results of the computational analysis were validated by FOXM1 knockdown experiments, which resulted in suppressed cell proliferation and enhanced therapeutic sensitivity in prostate cancer cells. The present findings demonstrated that chromatin accessibility and TF activity may be associated with therapeutic resistance in prostate cancer. Additionally, these results provide the basis for future investigations aimed at understanding the molecular mechanisms of drug resistance and developing novel therapeutic approaches for prostate cancer.

Isocitrate dehydrogenase 1 (IDH1) is a metabolic enzyme that converts isocitrate to α-ketoglutarate in cells. However, research on IDH1 is more focused on the metabolite D-2-hydroxyglutarate than the cellular roles of the IDH1 protein. Metabolic enzymes can moonlight by participating in diverse cellular processes in cancer cells. This moonlighting function of the metabolic enzymes can contribute to changes in gene expression. It is unknown whether IDH1 associates with any transcription factor. We asked whether IDH1 coordinates with forkhead box protein M1 (FOXM1) in mitotic cells to regulate late genes expression. We found that depletion of IDH1 reduces canonical FOXM1-target expression in mitotic cells. Also, IDH1 binds to FOXM1 and a subset of MuvB proteins, Lin-9 and Lin-54, in mitotic cells. Based on these observations, we suggest that IDH1 coordinates with FOXM1 in mitotic cells to regulate late genes expression.

The Hippo-YAP1 pathway is an evolutionally conserved signaling cascade that controls organ size and tissue regeneration. Dysregulation of Hippo-YAP1 signaling promotes initiation and progression of several types of cancer, including gastric cancer. As the Hippo-YAP1 pathway regulates expression of thousands of genes, it is important to establish which target genes contribute to the oncogenic program driven by YAP1 to identify strategies to circumvent it. In this study, we identified a vital role of forkhead box protein 4 (FOXP4) in YAP1-driven gastric carcinogenesis by maintaining stemness and promoting peritoneal metastasis. Loss of FOXP4 impaired gastric cancer spheroid formation and reduced stemness marker expression, whereas FOXP4 upregulation potentiated cancer cell stemness. RNA sequencing analysis revealed SOX12 as a downstream target of FOXP4, and functional studies established that SOX12 supports stemness in YAP1-induced carcinogenesis. A small-molecule screen identified 42-(2-tetrazolyl) rapamycin as a FOXP4 inhibitor, and targeting FOXP4 suppressed gastric cancer tumor growth and enhanced the efficacy of 5-fluorouracil chemotherapy in vivo. Collectively, these findings revealed that FOXP4 upregulation by YAP1 in gastric cancer regulates stemness and tumorigenesis by upregulating SOX12. Targeting the YAP1-FOXP4-SOX12 axis represents a potential therapeutic strategy for gastric cancer. Significance: Hippo-YAP1 signaling maintains stemness in gastric cancer by upregulating FOXP4, identifying FOXP4 as a stemness biomarker and therapeutic target that could help improve patient outcomes.

Forkhead box O4 (FOXO4), a human transcription factor, recognizes target DNA through its forkhead domain (FHD) while maintaining comparable binding affinity to non-target DNA. The conserved region 3 (CR3), a transactivation domain, modulates DNA binding kinetics to FHD and contributes to target DNA selection, but the underlying mechanism of this selection remains elusive. Using paramagnetic relaxation enhancement analysis, we observed a minor state of CR3 close to FHD in the presence of non-target DNA, a state absent when FHD interacts with target DNA. This minor state suggests that CR3 effectively masks the non-target DNA-binding interface on FHD. The interaction weakens significantly under high salt concentration, implying that CR3 or high salt concentrations can modulate electrostatic interactions with non-target DNA. Our 15N relaxation measurements revealed FHD's flexibility with non-target DNA and increased rigidity with target DNA binding. Our findings offer insights into the role of FOXO4 as a transcription initiator.

Periodontitis, a common chronic inflammatory disease, epitomizes a significant impairment in the host immune system and an imbalance of bone metabolism. Macrophage polarization, a dynamic process dictated by the microenvironment, intricately contributes to the interplay between the immune system and bone remodeling, namely the osteoimmune system. Forkhead box protein O1 (FoxO1) has been shown to play a dramatic role in mediating oxidative stress, bone mass, as well as cellular metabolism. Nevertheless, the function and underlying mechanisms of FoxO1 in regulating macrophage polarization-mediated osteogenesis in periodontitis remain to be further elucidated. Here, we found that FoxO1 expression was closely linked to periodontitis, accompanied by aggravated inflammation. Notably, FoxO1 knockdown skewed macrophage polarization from M1 to the antiinflammatory M2 phenotype under inflammatory conditions, which rescued the impaired osteogenic potential. Mechanistically, we revealed that the enhancement of the transcription of peroxisome proliferator-activated receptor (PPAR) signaling in FoxO1-knockdown macrophages. In agreement with this contention, GW9662, a specific inhibitor of PPAR-γ signaling, greatly aggravated macrophage polarization from M2 to the M1 phenotype and attenuated osteogenic potential under inflammatory conditions. Additionally, PPAR-γ signaling agonist rosiglitazone (RSG) was applied to address ligature-induced periodontitis with attenuated inflammation. Our data lend conceptual credence to the function of FoxO1 in mediating macrophage polarization-regulated osteogenesis which serves as a novel therapeutic target for periodontitis.

Late diagnosis is considered one of the main reasons of high mortality rate among cancer patients that results in therapeutic failure and tumor relapse. Therefore, it is needed to evaluate the molecular mechanisms associated with tumor progression to introduce efficient markers for the early tumor detection among cancer patients. The remarkable stability of microRNAs (miRNAs) in body fluids makes them potential candidates to use as the non-invasive tumor biomarkers in cancer screening programs. MiR-135b has key roles in prognosis and survival of cancer patients by either stimulating or inhibiting cell proliferation, invasion, and angiogenesis. Therefore, in the present review we assessed the molecular biology of miR-135b during tumor progression to introduce that as a novel tumor marker in cancer patients. It has been reported that miR-135b mainly acts as an oncogene by regulation of transcription factors, signaling pathways, drug response, cellular metabolism, and autophagy. This review paves the way to suggest miR-135b as a tumor marker and therapeutic target in cancer patients following the further clinical trials and animal studies.

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.

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.

To establish a computed tomography (CT)-based radiomics model to predict Fork head box M1(FOXM1) expression levels and develop a combined model for prognostic prediction in patients with clear cell renal cell carcinoma (ccRCC).

A total of 529 patients were utilized to assess the prognostic significance of FOXM1 expression and were subsequently categorized into low and high FOXM1 expression groups. 184 patients with CT images were randomly divided into training and validation cohorts. Radiomics signature (Rad-score) for predicting FOXM1 expression level was developed in the training cohort. The predictive performance was evaluated using receiver operating characteristic (ROC) curves. A clinical model based on clinical factors and a combined model incorporating clinical factors and Rad-score were developed to predict ccRCC prognosis using Cox regression analyses. The concordance index(C-index) was employed to assess and compare the predictive capabilities of the Rad-score, TNM stage, clinical model, and combined model. The likelihood ratio test was used to compare the models' performance.

The Rad-score demonstrated high predictive accuracy for high FOXM1 expression with areas under the ROC curves of 0.713 and 0.711 in the training and validation cohorts. In the training cohort, the C-indexes for the Rad-score, TNM Stage, clinical model, and combined model were 0.657, 0.711, 0.737, and 0.741, respectively. Correspondingly, in the validation cohort, the C-indexes were 0.670, 0.712, 0.736, and 0.745. The combined model had the highest C-index, significantly outperforming the other models.

The Rad-score accurately predicts FOXM1 expression levels and is an independent prognostic factor for ccRCC.

Alaska contains over 600 formerly used defense (FUD) sites, many of which serve as point sources of pollution. These sites are often co-located with rural communities that depend upon traditional subsistence foods, especially lipid-rich animals that bioaccumulate and biomagnify persistent organic pollutants (POPs). Many POPs are carcinogenic and endocrine-disrupting compounds that are associated with adverse health outcomes. Therefore, elevated exposure to POPs from point sources of pollution may contribute to disproportionate incidence of disease in arctic communities. We investigated PCB concentrations and the health implications of POP exposure in sentinel fishes collected near the Northeast Cape FUD site on Sivuqaq (St. Lawrence Island), Alaska. Sivuqaq residents are almost exclusively Yupik and rely on subsistence foods. At the request of the Sivuqaq community, we examined differential gene expression and developmental pathologies associated with exposure to POPs originating at the Northeast Cape FUD site. We found significantly higher levels of PCBs in Alaska blackfish (Dallia pectoralis) collected from contaminated sites downstream of the FUD site compared to fish collected from upstream reference sites. We compared transcriptomic profiles and histopathologies of these same blackfish. Blackfish from contaminated sites overexpressed genes involved in ribosomal and FoxO signaling pathways compared to blackfish from reference sites. Contaminated blackfish also had significantly fewer thyroid follicles and smaller pigmented macrophage aggregates. Conversely, we found that ninespine stickleback (Pungitius pungitius) from contaminated sites exhibited thyroid follicle hyperplasia. Despite our previous research reporting transcriptomic and endocrine differences in stickleback from contaminated vs. reference sites, we did not find significant differences in kidney or gonadal histomorphologies. Our results demonstrate that contaminants from the Northeast Cape FUD site are associated with altered gene expression and thyroid development in native fishes. These results are consistent with our prior work demonstrating disruption of the thyroid hormone axis in Sivuqaq residents.

Recent progresses in diagnostic and therapeutic methods have significantly improved prognosis in cancer patients. However, cancer is still considered as one of the main causes of human deaths in the world. Late diagnosis in advanced tumor stages can reduce the effectiveness of treatment methods and increase mortality rate of cancer patients. Therefore, investigating the molecular mechanisms of tumor progression can help to introduce the early diagnostic markers in these patients. MicroRNA (miRNAs) has an important role in regulation of pathophysiological cellular processes. Due to their high stability in body fluids, they are always used as the non-invasive markers in cancer patients. Since, miR-363 deregulation has been reported in a wide range of cancers, we discussed the role of miR-363 during tumor progression and metastasis. It has been reported that miR-363 has mainly a tumor suppressor function through the regulation of transcription factors, apoptosis, cell cycle, and structural proteins. MiR-363 also affected the tumor progression via regulation of various signaling pathways such as WNT, MAPK, TGF-β, NOTCH, and PI3K/AKT. Therefore, miR-363 can be introduced as a probable therapeutic target as well as a non-invasive diagnostic marker in cancer patients.

Covering: up to 2024Ribosomally synthesised and post-translationally modified peptides (RiPPs) comprise a substantial group of peptide natural products exhibiting noteworthy bioactivities ranging from antiinfective to anticancer and analgesic effects. Furthermore, RiPP biosynthetic pathways represent promising production routes for complex peptide drugs, and the RiPP technology is well-suited for peptide engineering to produce derivatives with specific functions. Thus, RiPP natural products possess features that render them potentially ideal candidates for drug discovery and development. Nonetheless, only a small number of RiPP-derived compounds have successfully reached the market thus far. This review initially outlines the therapeutic opportunities that RiPP-based compounds can offer, whilst subsequently discussing the limitations that require resolution in order to fully exploit the potential of RiPPs towards the development of innovative drugs.

Tebuconazole (TEB) is a commonly used fungicide that inhibits the aromatase Cyp19A and downregulates the transcription factor forkhead box L2 (FoxL2), leading to male-biased sex differentiation in zebrafish larvae. However, the specific mechanism by which FoxL2 functions following TEB exposure remains unclear. In this study, the phosphorylation sites and kinase-specific residues in zebrafish FoxL2 protein (zFoxL2) were predicted. Subsequently, recombinant zFoxL2 was prepared via prokaryotic expression, and a polyclonal rabbit-anti-zFoxL2 antibody was generated. Zebrafish fibroblast (ZF4) cells were exposed to 100-μM TEB alone for 8 h, after which changes in the expression of genes involved in the foxl2 regulatory pathway (akt1, pi3k, cyp19a1b, c/ebpb and sox9a) were detected. When co-exposed to 1-μM estradiol and 100-μM TEB, the expression of these key genes tended to be restored. Interestingly, TEB did not affect the expression of the foxl2 gene or protein but it significantly suppressed the phosphorylation of FoxL2 (pFoxL2) at serine 238 (decreased by 43.64 %, p = 0.009). Co-immunoprecipitation assays showed that, following exposure to 100-μM TEB, the total precipitated proteins in ZF4 cells decreased by 17.02 % (p = 0.029) and 31.39 % (p = 0.027) in the anti-zFoxL2 antibody group and anti-pFoxL2 (ser238) antibody group, respectively, indicating that TEB suppressed the capacity of the FoxL2 protein to bind to other proteins via repression of its own phosphorylation. The pull-down assay confirmed this conclusion. This study preliminarily elucidated that the foxl2 gene functions via post-translational regulation through hypophosphorylation of its encoded protein during TEB-induced male-biased sex differentiation.

The high mortality rate in cancer patients is always one of the main challenges of the health systems globally. Several factors are involved in the high rate of cancer related mortality, including late diagnosis and drug resistance. Cancer is mainly diagnosed in the advanced stages of tumor progression that causes the failure of therapeutic strategies and increases the death rate in these patients. Therefore, assessment of the molecular mechanisms associated with the occurrence of cancer can be effective to introduce early tumor diagnostic markers. MicroRNAs (miRNAs) as the stable non-coding RNAs in the biological body fluids are involved in regulation of cell proliferation, migration, and apoptosis. MiR-532 deregulation has been reported in different tumor types. Therefore, in the present review we discussed the role of miR-532 during tumor growth. It has been shown that miR-532 has mainly a tumor suppressor role through the regulation of transcription factors, chemokines, and signaling pathways such as NF-kB, MAPK, PI3K/AKT, and WNT. In addition to the independent role of miR-532 in regulation of cellular processes, it also functions as a mediator of lncRNAs and circRNAs. Therefore, miR-532 can be considered as a non-invasive diagnostic/prognostic marker as well as a therapeutic target in cancer patients.

The steroid hormone 17β-estradiol (E2) has a significant impact on the development and progression of tumors. E2 stimulates tumor cell growth and metabolism, leading to an increase in reactive oxygen species (ROS) production. However, the rise in ROS levels is not sufficient to cause severe harm to cancer cells. and the mechanisms that regulate ROS are not well understood. Since FOXM1 plays a crucial role in the production of ROS, we aimed to investigate the impact of E2 on oxidative stress and the involvement of FOXM1 in the Ishikawa endometrial cancer cell line. Our research revealed that E2 controls the levels of ROS inside cells and safeguards them from apoptosis by promoting the expression of FOXM1. We observed a decrease in the expression of FOXM1 alongside an increase in oxidative damage. Moreover, cells demonstrated elevated levels of FOXM1 and ERα upon E2 treatment. Overall, our findings suggest that E2 prevents apoptosis induced by oxidative stress in endometrial cancer cells by encouraging the expression of FOXM1, potentially affecting ERα.

Prostate cancer (PCa) is a widespread global health concern characterized by elevated rates of occurrence, and there is a need for novel therapeutic targets to enhance patient outcomes. FOXS1 is closely linked to different cancers, but its function in PCa is still unknown. The expression of FOXS1, its prognostic role, clinical significance in PCa, and the potential mechanism by which FOXS1 affects PCa progression were investigated through bioinformatics analysis utilizing public data. The levels of FOXS1 and HILPDA were evaluated in clinical PCa samples using various methods, such as western blotting, immunohistochemistry, and qRT-PCR. To examine the function and molecular mechanisms of FOXS1 in PCa, a combination of experimental techniques including CCK-8 assay, flow cytometry, wound-healing assay, Transwell assay, and Co-IP assay were employed. The FOXS1 expression levels were significantly raised in PCa, correlating strongly with tumor aggressiveness and an unfavorable prognosis. Regulating FOXS1 expression, whether upregulating or downregulating it, correspondingly enhanced or inhibited the growth, migration, and invasion capabilities of PCa cells. Mechanistically, we detected a direct interaction between FOXS1 and HILPDA, resulting in the pathway activation of FAK/PI3K/AKT and facilitation EMT in PCa cells. FOXS1 collaborates with HILPDA to initiate EMT, thereby facilitating the PCa progression through the FAK/PI3K/AKT pathway activation.

Forkhead box protein M1 (FOXM1) is often overexpressed in human cancers and strongly associated with therapy resistance and less good patient survival. The chemotherapy options for patients with the most aggressive types of solid cancers remain very limited because of the acquired drug resistance, making the therapy less effective. NPM1 mutation through the inactivation of FOXM1 via FOXM1 relocalization to the cytoplasm confers more favorable treatment outcomes for AML patients, confirming FOXM1 as a crucial target to overcome drug resistance. Pharmacological inhibition of FOXM1 could be a promising approach to sensitize therapy-resistant cancers. Here, we explore a novel FOXM1 inhibitor STL001, a first-generation modification drug of our previously reported FOXM1 inhibitor STL427944. STL001 preserves the mode of action of the STL427944; however, STL001 is up to 50 times more efficient in reducing FOXM1 activity in a variety of solid cancers. The most conventional cancer therapies studied here induce FOXM1 overexpression in solid cancers. The therapy-induced FOXM1 overexpression may explain the failure or reduced efficacy of these drugs in cancer patients. Interestingly, STL001 increased the sensitivity of cancer cells to conventional cancer therapies by suppressing both the high-endogenous and drug-induced FOXM1. Notably, STL001 does not provide further sensitization to FOXM1-KD cancer cells, suggesting that the sensitization effect is conveyed specifically through FOXM1 suppression. RNA-seq and gene set enrichment studies revealed prominent suppression of FOXM1-dependent pathways and gene ontologies. Also, gene regulation by STL001 showed extensive overlap with FOXM1-KD, suggesting a high selectivity of STL001 toward the FOXM1 regulatory network. A completely new activity of FOXM1, mediated through steroid/cholesterol biosynthetic process and protein secretion in cancer cells was also detected. Collectively, STL001 offers intriguing translational opportunities as combination therapies targeting FOXM1 activity in a variety of human cancers driven by FOXM1.

Dysregulated expression of Forkhead Box N2 (FOXN2) has been detected in various cancer types. However, the underlying mechanisms by which FOXN2 contributes to the onset and progression of gastric cancer (GC) remain largely unexplored. This study aimed to elucidate the potential role of FOXN2 within GC, its downstream molecular mechanisms, and its feasibility as a novel serum biomarker for GC.

Tissue samples from GC patients and corresponding non-cancerous tissues were collected. Peripheral blood samples were obtained from GC patients and healthy controls. The expression of FOXN2 was determined using quantitative real-time PCR, western blotting, and immunohistochemistry. The expression of FOXN2 in GC cells was modulated by transfection with small interfering RNA (siRNA) or the pcDNA 3.1 expression vector. Cell proliferation was assessed using the Cell Counting Kit-8 and 5-ethynyl-2'-deoxyuridine incorporation assays. The migratory and invasive capacities of cells were evaluated by Transwell assays, apoptosis rates were measured by flow cytometry, and the expression of proliferative, apoptotic, and epithelial-mesenchymal transition (EMT) markers were assessed by western blot analysis.

FOXN2 was found to be overexpressed in the serum, tissues, and cells of GC, correlating with distant metastasis and TNM staging. FOXN2 demonstrated diagnostic value in differentiating GC patients from healthy individuals, with higher levels of FOXN2 being indicative of poorer survival rates. Silencing FOXN2 in vitro inhibited the proliferation, invasion, migration, and EMT of GC cells, while promoting apoptosis. FOXN2 was shown to regulate the transforming growth factor-beta (TGFβ) receptor signaling pathway in GC cells via its interaction with Partitioning Defective 6 Homolog Alpha (PARD6A).

In summary, our data suggest that FOXN2 acts as an oncogenic factor in GC, modulating the TGFβ pathway by binding to PARD6A, thereby influencing gastric carcinogenesis. This study underscores the functional significance of FOXN2 as a potential serum biomarker and therapeutic target in GC.

In recent decades, substantial advancements in epigenetics have unveiled a profound understanding of its mechanisms in tumorigenesis and have offered promising strategies for epigenetic therapy in cancer patients. In our study, through bioinformatics analysis, we discovered a significant downregulation and hypermethylation of FOXI2 in clear cell renal cell carcinoma (ccRCC), while the expression in chromophobe cell carcinoma (chRCC) exhibited the opposite trend. Moreover, we established a strong correlation between FOXI2 expression levels and the prognosis of ccRCC. Gene enrichment analysis and cell function experiments unequivocally demonstrate that FOXI2 possesses the capability to induce cell cycle arrest and inhibit cell proliferation. Our research findings demonstrate that the expression of FOXI2 in ccRCC is under the regulation of promoter hypermethylation. Furthermore, in vitro experiments have conclusively shown that the overexpression of FOXI2 induces cell cycle arrest and inhibits cell proliferation.

The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1's canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy.

Breast cancer is a common malignancy with the highest mortality rate among women worldwide. Its incidence is on the rise year after year, accounting for more than one-tenth of new cancers worldwide. Increasing evidence suggests that forkhead box (FOX) transcription factors play an important role in the occurrence and development of breast cancer. However, little is known about the relationship between the expression, prognostic value, function, and immune infiltration of FOX transcription factors in tumor microenvironment. We used bioinformatics to investigate expression and function of FOX factor in breast cancer. Our results revealed the expression levels of FOXA1 and FOXM1 were significantly higher in breast cancer tissues than in normal tissues. The high expression of mRNA in FOXA1 (P < .05), FOXM1 (P < .01), and FOXP1 (P < .05) groups was related to tumor stage. Survival analysis results showed that increased FOXP1 mRNA levels were significantly associated with overall survival (OS), recurrence-free survival (RFS), and distant metastasis-free survival (DMFS) in all patients with breast cancer (P < .05). Patients with the FOXA1 high-expression group had better RFS and DMFS than the low-expression group (P < .05), while patients with FOXM1 high-expression group had worse RFS, OS, and DMFS than the low-expression group (P < .05). Meanwhile, mutation analysis showed that genetic alterations in FOX transcription factors were significantly associated with shorter OS and progression-free survival (P < .05), but not with disease-free survival (P = .710) in patients with breast cancer. FOXP1, FOXA1, and FOXM1 may be used as potential biomarkers to predict the prognosis of patients with breast cancer. Functional enrichment indicated that FOX was mainly involved in cell division, cell senescence, cell cycle, and prolactin signaling pathway. In patients with breast cancer, FOXC2 expression was negatively correlated with the infiltration of B cells and positively correlated with the infiltration of neutrophils and dendritic cells. However, FOXM1 was negatively correlated with the infiltration of CD8 + T cells and macrophages and positively correlated with the infiltration of neutrophils and dendritic cells. These findings provided novel insights into the screening of prognostic biomarkers of the FOX family in breast cancer and laid a foundation for further research on the immune infiltration of the FOX transcription factor family members in tumors.

As key developmental regulators, HOX cluster genes have varied and context-specific roles in normal and malignant hematopoiesis. A complex interaction of transcription factors, epigenetic regulators, long non-coding RNAs and chromatin structural changes orchestrate HOX expression in leukemia cells. In this review we summarize molecular mechanisms underlying HOX regulation in clinical subsets of AML, with a focus on NPM1 mutated (NPM1mut) AML comprising a third of all AML patients. While the leukemia initiating function of the NPM1 mutation is clearly dependent on HOX activity, the favorable treatment responses in these patients with upregulation of HOX cluster genes is a poorly understood paradoxical observation. Recent data confirm FOXM1 as a suppressor of HOX activity and a well-known binding partner of NPM suggesting that FOXM1 inactivation may mediate the effect of cytoplasmic NPM on HOX upregulation. Conversely the residual nuclear fraction of mutant NPM has also been recently shown to have chromatin modifying effects permissive to HOX expression. Recent identification of the menin-MLL interaction as a critical vulnerability of HOX-dependent AML has fueled the development of menin inhibitors that are clinically active in NPM1 and MLL rearranged AML despite inconsistent suppression of the HOX locus. Insights into context-specific regulation of HOX in AML may provide a solid foundation for targeting this common vulnerability across several major AML subtypes.

Tumor adaptation or selection is thought to underlie therapy resistance in glioma. To investigate longitudinal epigenetic evolution of gliomas in response to therapeutic pressure, we performed an epigenomic analysis of 132 matched initial and recurrent tumors from patients with IDH-wildtype (IDHwt) and IDH-mutant (IDHmut) glioma. IDHwt gliomas showed a stable epigenome over time with relatively low levels of global methylation. The epigenome of IDHmut gliomas showed initial high levels of genome-wide DNA methylation that was progressively reduced to levels similar to those of IDHwt tumors. Integration of epigenomics, gene expression, and functional genomics identified HOXD13 as a master regulator of IDHmut astrocytoma evolution. Furthermore, relapse of IDHmut tumors was accompanied by histologic progression that was associated with survival, as validated in an independent cohort. Finally, the initial cell composition of the tumor microenvironment varied between IDHwt and IDHmut tumors and changed differentially following treatment, suggesting increased neoangiogenesis and T-cell infiltration upon treatment of IDHmut gliomas. This study provides one of the largest cohorts of paired longitudinal glioma samples with epigenomic, transcriptomic, and genomic profiling and suggests that treatment of IDHmut glioma is associated with epigenomic evolution toward an IDHwt-like phenotype.

Standard treatments are related to loss of DNA methylation in IDHmut glioma, resulting in epigenetic activation of genes associated with tumor progression and alterations in the microenvironment that resemble treatment-naïve IDHwt glioma.

Hemifacial macrosomia (HFM, OMIM 164210) is a complex and highly heterogeneous disease. FORKHEAD BOX I3 (FOXI3) is a susceptibility gene for HFM, and mice with loss of function of Foxi3 did exhibit a phenotype similar to craniofacial dysmorphism. However, the specific pathogenesis of HFM caused by FOXI3 deficiency remains unclear till now.

In this study, we first constructed a Foxi3 deficiency (Foxi3-/- ) mouse model to verify the craniofacial phenotype of Foxi3-/- mice, and then used RNAseq data for gene differential expression analysis to screen candidate pathogenic genes, and conducted gene expression verification analysis using quantitative real-time PCR.

By observing the phenotype of Foxi3-/- mice, we found that craniofacial dysmorphism was present. The results of comprehensive bioinformatics analysis suggested that the craniofacial dysmorphism caused by Foxi3 deficiency may be involved in the PI3K-Akt signaling pathway. Quantitative real-time PCR results showed that the expression of PI3K-Akt signaling pathway-related gene Akt2 was significantly increased in Foxi3-/- mice.

The craniofacial dysmorphism caused by the deficiency of Foxi3 may be related to the expression of Akt2 and PI3K-Akt signaling pathway. This study laid a foundation for understanding the function of FOXI3 and the pathogenesis and treatment of related craniofacial dysmorphism caused by FOXI3 dysfunction.

Successful implantation requires coordinated migration and invasion of trophoblast cells into a receptive endometrium. Reduced forkhead box M1 (FOXM1) expression limits trophoblast migration and angiogenesis in choriocarcinoma cell lines, and in a rat model, placental FOXM1 protein expression was significantly upregulated in the early stages of pregnancy compared to term pregnancy. However, the precise role of FOXM1 in implantation events remains unknown. By analyzing mice blastocysts at embryonic day (E3.5), we have demonstrated that FOXM1 is expressed as early as the blastocyst stage, and it is expressed in the trophectoderm of the blastocyst. Since controlled oxygen tension is determinant for achieving normal implantation and placentation and a chronic hypoxic environment leads to shallow trophoblast invasion, we evaluated if FOXM1 expression changes in response to different oxygen tensions in the HTR-8/SVneo first trimester human trophoblast cell line and observed that FOXM1 expression was significantly higher when trophoblast cells were cultured at 3% O2, which coincides with oxygen concentrations in the uteroplacental interface at the time of implantation. Conversely, FOXM1 expression diminished in response to 1% O2 that resembles a hypoxic environment in utero. Migration and angiogenesis were assessed following FOXM1 knockdown and overexpression at 3% O2 and 1% O2, respectively, in HTR-8/SVneo cells. FOXM1 overexpression increased transmigration ability and tubule formation. Using a 3D trophoblast invasion model with trophospheres from HTR-8/SVneo cells cultured on a layer of MATRIGEL and of mesenchymal stem cells isolated from menstrual fluid, we observed that trophospheres obtained from 3D trophoblast invasion displayed higher FOXM1 expression compared with pre-invasion trophospheres. Moreover, we have also observed that FOXM1-overexpressing trophospheres increased trophoblast invasion compared with controls. HTR-8/SVneo-FOXM1-depleted cells led to a downregulation of PLK4, VEGF, and MMP2 mRNA expression. Our current findings suggest that FOXM1 participates in embryo implantation by contributing to trophoblast migration and early trophoblast invasion, by inducing transcription activation of genes involved in these processes. Maternal-fetal communication is crucial for trophoblast invasion, and maternal stromal cells may induce higher levels of FOXM1 in trophoblast cells.