FOXA1 co-activates circODC1 and ODC1 in HPV-positive cervical cancer cell growth.

As demonstrated in previous research, hsa_circ_0052602 (circODC1) is dynamically expressed in HPV-positive cervical cancer (CC). CircODC1 expression was quantified using qRT-PCR, and its role in CC cell growth was assessed via loss-of-function assays. Interactions between miR-607 and circODC1 or ODC1 were confirmed using bioinformatics and mechanistic assays. The association of FOXA1 with the circODC1 promoter was validated through ChIP and luciferase reporter assays. CircODC1 was highly expressed in HPV-positive CC cell lines, and its depletion significantly impeded malignant processes such as proliferation, migration, and invasion. We found that ODC1 also played an oncogenic role in HPV-positive CC cells. CircODC1 was shown to positively regulate ODC1 as a ceRNA, competitively binding to miR-607 to counteract its suppression of ODC1. HPV-associated FOXA1 was identified as a potential transcription factor of circODC1. Restoration experiments showed that overexpression of circODC1 could counterbalance the inhibitory effect of FOXA1 knockdown. These findings offer new insights into therapeutic strategies for HPV-positive CC patients.

Knockdown of KBTBD7 attenuates septic lung injury by inhibiting ferroptosis and improving mitochondrial dysfunction.

Lung injury in sepsis is caused by an excessive inflammatory response caused by the entry of pathogenic microorganisms into the body. It is also accompanied by the production of large amounts of ROS. Ferroptosis and mitochondrial dysfunction have also been shown to be related to sepsis. Finding suitable sepsis therapeutic targets is crucial for sepsis research. BTB domain-containing protein 7 (KBTBD7) is involved in regulating inflammatory responses, but its role and mechanism in the treatment of septic lung injury are still unclear. In this study, we evaluated the role and related mechanisms of KBTBD7 in septic lung injury. In in vitro studies, we established an in vitro model by inducing human alveolar epithelial cells with lipopolysaccharide (LPS) and found that KBTBD7 was highly expressed in the in vitro model. KBTBD7 knockdown could reduce the inflammatory response by inhibiting the secretion of pro-inflammatory factors and inhibit the production of ROS, ferroptosis and mitochondrial dysfunction. Mechanistic studies show that KBTBD7 interacts with FOXA1, promotes FOXA1 expression, and indirectly inhibits SLC7A11 transcription. In vivo studies have shown that knocking down KBTBD7 improves lung tissue damage in septic lung injury mice, inhibits inflammatory factors, ROS production and ferroptosis. Taken together, knockdown of KBTBD7 shows an alleviating effect on septic lung injury in vitro and in vivo, providing a potential therapeutic target for the treatment of septic lung injury.

Expression of BCL2, TP53, FOXA1, and GATA3 in pTa bladder cancer recurrence.

OBJECTIVES: In this study, we analyzed pTa bladder cancer (BC) for molecular markers BCL2, TP53, FOXA1, and GATA3 in relation to cancer recurrence. METHODS: We analyzed samples of 79 patients with the pTa stage of BC using a real-time polymerase chain reaction (real-time PCR) between September 2018 and September 2020. The expression levels of BCL2, TP53, FOXA1, and GATA3 were compared with homologous non-tumor bladder tissue. RESULTS: Expression of FOXA1, GATA3, and TP53 was significantly higher (p<0.01) in NMIBC samples compared to homologous non-tumor tissue. The expression of TP53 and FOXA1 in pTa was significantly lower (p<0.01) in the high-grade (HG) tumor when compared to the low-grade (LG) tumor. In contrast, the relative quantification (RQ) of GATA3 was significantly higher (p<0.01) in HG pTa. Patients with recurrence (pTa=33) had significantly higher expression of TP53, and GATA3 (p<0.01), and the gene of FOXA1 (p<0.01) had a significantly lower expression when compared to pTa tumors without recurrence. The expression of Bcl-2 was not statistically significant. CONCLUSION: Our results, indicate, that comparing expression levels of these genes in cancer and cancer-free tissue could provide valuable data, as patients with pTa BC recurrence within up to 54 months of follow-up had a significantly higher RQ of TP53, GATA3, and FOXA1 when compared to pTa BC patients without recurrence (Tab. 2, Fig. 8, Ref. 54). Text in PDF www.elis.sk Keywords: bladder cancer, gene expression, recurrence, GATA3, FOXA1, TP53, BCL2.

FOXA1/UBE2T Inhibits CD8+T Cell Activity by Inducing Mediates Glycolysis in Lung Adenocarcinoma.

BACKGROUND: Immune escape is a key factor influencing survival rate of lung adenocarcinoma (LUAD) patients, but molecular mechanism of ubiquitin binding enzyme E2T (UBE2T) affecting immune escape of LUAD remains unclear. The objective was to probe role of UBE2T in LUAD. METHODS: Bioinformatics means were adopted for analyzing UBE2T and forkhead box A1 (FOXA1) expression in LUAD tissues, the gene binding sites, the pathway UBE2T regulates, and the correlation between UBE2T and glycolysis genes. Dual luciferase and chromatin immunoprecipitation (ChIP) assays were conducted for validating the binding relationship between the two genes. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot were employed to evaluate UBE2T, FOXA1, and programmed death ligand 1 (PD-L1) levels in cancer cells. MTT assay was conducted for detecting cell viability. Cytotoxicity assay detected CD8+T cell toxicity. Cytokine expression was assayed by enzyme linked immunosorbent assay (ELISA). Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were assayed by extracellular flow analyzer. Glycolytic gene expression was analyzed by qRT-PCR, and glycolysis-related indicators were detected by ELISA. Immunohistochemistry (IHC) detected CD8+T cell infiltration in tumor tissues. RESULTS: FOXA1 and UBE2T were up-regulated in LUAD, and a binding site existed between UBE2T and FOXA1. Overexpressing UBE2T could increase PD-L1 expression and inhibit toxicity of CD8+T cells to LUAD cells. Overexpressing UBE2T repressed CD8+T cell activity in LUAD by activating the glycolysis pathway, and the addition of glycolysis inhibitor 2-deoxy-d-glucose (2-DG) reversed the above results. Mechanistically, FOXA1 promoted the immune escape of LUAD by up-regulating UBE2T and thus mediating glycolysis. In vivo experiments revealed that UBE2T knockdown hindered tumor growth, inhibited PD-L1 expression, and facilitated CD8+T cell infiltration. CONCLUSION: FOXA1 up-regulated the expression of UBE2T, which activated glycolysis, and thus inhibited activity of CD8+T cells, causing immune escape of LUAD.

Wnt/ß-catenin signaling regulates amino acid metabolism through the suppression of CEBPA and FOXA1 in liver cancer cells.

Deregulation of the Wnt/ß-catenin pathway is associated with the development of human cancer including colorectal and liver cancer. Although we previously showed that histidine ammonia lyase (HAL) was transcriptionally reduced by the ß-catenin/TCF complex in liver cancer cells, the mechanism(s) of its down-regulation by the complex remain to be clarified. In this study, we search for the transcription factor(s) regulating HAL, and identify CEBPA and FOXA1, two factors whose expression is suppressed by the knockdown of ß-catenin or TCF7L2. In addition, RNA-seq analysis coupled with genome-wide mapping of CEBPA- and FOXA1-binding regions reveals that these two factors also increase the expression of arginase 1 (ARG1) that catalyzes the hydrolysis of arginine. Metabolome analysis discloses that activated Wnt signaling augments intracellular concentrations of histidine and arginine, and that the signal also increases the level of lactic acid suggesting the induction of the Warburg effect in liver cancer cells. Further analysis reveals that the levels of metabolites of the urea cycle and genes coding its related enzymes are also modulated by the Wnt signaling. These findings shed light on the altered cellular metabolism in the liver by the Wnt/ß-catenin pathway through the suppression of liver-enriched transcription factors including CEBPA and FOXA1.

Clinically-observed FOXA1 mutations upregulate SEMA3C through transcriptional derepression in prostate cancer.

FOXA1 is a pioneer transcription factor that is frequently mutated in prostate, breast, bladder, and salivary gland malignancies. Indeed, metastatic castration-resistant prostate cancer (mCRPC) commonly harbour FOXA1 mutations with a prevalence of 35%. However, despite the frequent recurrence of FOXA1 mutations in prostate cancer, the mechanisms by which FOXA1 variants drive its oncogenic effects are still unclear. Semaphorin 3C (SEMA3C) is a secreted autocrine growth factor that drives growth and treatment resistance of prostate and other cancers and is known to be regulated by both AR and FOXA1. In the present study, we characterize FOXA1 alterations with respect to its regulation of SEMA3C. Our findings reveal that FOXA1 alterations lead to elevated levels of SEMA3C both in prostate cancer specimens and in vitro. We further show that FOXA1 negatively regulates SEMA3C via intronic cis elements, and that mutations in FOXA1 forkhead domain attenuate its inhibitory function in reporter assays, presumably by disrupting DNA binding of FOXA1. Our findings underscore the key role of FOXA1 in prostate cancer progression and treatment resistance by regulating SEMA3C expression and suggest that SEMA3C may be a driver of growth and tumor vulnerability of mCRPC harboring FOXA1 alterations.

Staufen1 Represses the FOXA1-Regulated Transcriptome by Destabilizing FOXA1 mRNA in Colorectal Cancer Cells.

Transcription factors play key roles in development and disease by controlling gene expression. Forkhead box A1 (FOXA1), is a pioneer transcription factor essential for mouse development and functions as an oncogene in prostate and breast cancer. In colorectal cancer (CRC), FOXA1 is significantly downregulated and high FOXA1 expression is associated with better prognosis, suggesting potential tumor suppressive functions. We therefore investigated the regulation of FOXA1 expression in CRC, focusing on well-differentiated CRC cells, where FOXA1 is robustly expressed. Genome-wide RNA stability assays identified FOXA1 as an unstable mRNA in CRC cells. We validated FOXA1 mRNA instability in multiple CRC cell lines and in patient-derived CRC organoids, and found that the FOXA1 3'UTR confers instability to the FOXA1 transcript. RNA pulldowns and mass spectrometry identified Staufen1 (STAU1) as a potential regulator of FOXA1 mRNA. Indeed, STAU1 knockdown resulted in increased FOXA1 mRNA and protein expression due to increased FOXA1 mRNA stability. Consistent with these data, RNA-seq following STAU1 knockdown in CRC cells revealed that FOXA1 targets were upregulated upon STAU1 knockdown. Collectively, this study uncovers a molecular mechanism by which FOXA1 is regulated in CRC cells and provides insights into our understanding of the complex mechanisms of gene regulation in cancer.

Atypical inflammatory kinase IKBKE phosphorylates and inactivates FoxA1 to promote liver tumorigenesis.

Physiologically, FoxA1 plays a key role in liver differentiation and development, and pathologically exhibits an oncogenic role in prostate and breast cancers. However, its role and upstream regulation in liver tumorigenesis remain unclear. Here, we demonstrate that FoxA1 acts as a tumor suppressor in liver cancer. Using a CRISPR-based kinome screening approach, noncanonical inflammatory kinase IKBKE has been identified to inhibit FoxA1 transcriptional activity. Notably, IKBKE directly binds to and phosphorylates FoxA1 to reduce its complex formation and DNA interaction, leading to elevated hepatocellular malignancies. Nonphosphorylated mimic Foxa1 knock-in mice markedly delay liver tumorigenesis in hydrodynamic transfection murine models, while phospho-mimic Foxa1 knock-in phenocopy Foxa1 knockout mice to exhibit developmental defects and liver inflammation. Notably, Ikbke knockout delays diethylnitrosamine (DEN)-induced mouse liver tumor development. Together, our findings not only reveal FoxA1 as a bona fide substrate and negative nuclear effector of IKBKE in hepatocellular carcinioma (HCC) but also provide a promising strategy to target IKBEK for HCC therapy.

Chromatin accessibility and pioneer factor FOXA1 restrict glucocorticoid receptor action in prostate cancer.

Treatment of prostate cancer relies predominantly on the inhibition of androgen receptor (AR) signaling. Despite the initial effectiveness of the antiandrogen therapies, the cancer often develops resistance to the AR blockade. One mechanism of the resistance is glucocorticoid receptor (GR)-mediated replacement of AR function. Nevertheless, the mechanistic ways and means how the GR-mediated antiandrogen resistance occurs have remained elusive. Here, we have discovered several crucial features of GR action in prostate cancer cells through genome-wide techniques. We detected that the replacement of AR by GR in enzalutamide-exposed prostate cancer cells occurs almost exclusively at pre-accessible chromatin sites displaying FOXA1 occupancy. Counterintuitively to the classical pioneer factor model, silencing of FOXA1 potentiated the chromatin binding and transcriptional activity of GR. This was attributed to FOXA1-mediated repression of the NR3C1 (gene encoding GR) expression via the corepressor TLE3. Moreover, the small-molecule inhibition of coactivator p300's enzymatic activity efficiently restricted GR-mediated gene regulation and cell proliferation. Overall, we identified chromatin pre-accessibility and FOXA1-mediated repression as important regulators of GR action in prostate cancer, pointing out new avenues to oppose steroid receptor-mediated antiandrogen resistance.

Neuroprotective role of FOXA1 in Parkinson's disease: Involvements of NF1 transcription activation and MAPK signaling pathway inhibition.

Forkhead box A1 (FOXA1), a member of the forkhead family of transcription factors, plays a crucial role in the development of various organ systems and exhibits neuroprotective properties. This study aims to investigate the effect of FOXA1 on Parkinson's disease (PD) and unravel the underlying mechanism. Transcriptome analysis of PD was conducted using three GEO datasets to identify aberrantly expressed genes. A mouse model of PD was generated by injecting neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), resulting in reduced FOXA1 expression. FOXA1 decline was also observed in 1-methyl-4-phenylpyridinium-treated SH-SY5Y cells. Artificial upregulation of FOXA1 improved motor abilities of mice according to rotarod and pole tests, and it mitigated tissue damage, cell loss, and neuronal damage in the mouse substantia nigra or in vitro. FOXA1 was found to bind to the neurofibromin 1 (NF1) promoter, thereby inducing its transcription and inactivating the mitogen-activated protein kinase (MAPK) signaling pathway. Further experimentation revealed that silencing NF1 in mice or SH-SY5Y cells counteracted the neuroprotective effects of FOXA1. In conclusion, this research suggests that FOXA1 activates NF1 transcription and inactivates the MAPK signaling pathway, ultimately ameliorating neuronal damage and motor disability in PD. The findings may offer novel ideas in the field of PD management.

FOXA1 forms biomolecular condensates that unpack condensed chromatin to function as a pioneer factor.

Eukaryotic DNA is packaged into chromatin in the nucleus, restricting the binding of transcription factors (TFs) to their target DNA sites. FOXA1 functions as a pioneer TF to bind condensed chromatin and initiate the opening of local chromatin for gene expression. However, the principles of FOXA1 recruitment and how it subsequently unpacks the condensed chromatin remain elusive. Here, we revealed that FOXA1 intrinsically forms submicron-sized condensates through its N- and C-terminal intrinsically disordered regions (IDRs). Notably, both IDRs enable FOXA1 to dissolve the condensed chromatin. In addition, the DNA-binding capacity of FOXA1 contributes to its ability to both form condensates and dissolve condensed chromatin. Further genome-wide investigation showed that IDRs enable FOXA1 to bind and unpack the condensed chromatin to regulate the proliferation and migration of breast cancer cells. This work provides a principle of how pioneer TFs function to initiate competent chromatin states using their IDRs.

Unveiling the Molecular Landscape of FOXA1 Mutant Prostate Cancer: Insights and Prospects for Targeted Therapeutic Strategies.

Prostate cancer continues to pose a global health challenge as one of the most prevalent malignancies. Mutations of the Forkhead box A1 (FOXA1) gene have been linked to unique oncogenic features in prostate cancer. In this study, we aimed to unravel the intricate molecular characteristics of FOXA1 mutant prostate cancer through comprehensive in silico analysis of transcriptomic data from The Cancer Genome Atlas (TCGA). A comparison between FOXA1 mutant and control groups unearthed 1525 differentially expressed genes (DEGs), which map to eight intrinsic and six extrinsic signaling pathways. Interestingly, the majority of intrinsic pathways, but not extrinsic pathways, were validated using RNA-seq data of 22Rv1 cells from the GEO123619 dataset, suggesting complex biology in the tumor microenvironment. As a result of our in silico research, we identified novel therapeutic targets and potential drug candidates for FOXA1 mutant prostate cancer. KDM1A, MAOA, PDGFB, and HSP90AB1 emerged as druggable candidate targets, as we found that they have approved drugs throughout the drug database CADDIE. Notably, as most of the approved drugs targeting MAOA and KDM1A were monoamine inhibitors used for mental illness or diabetes, we suggest they have a potential to cure FOXA1 mutant primary prostate cancer without lethal side effects.

Colonic L-cell impairment in aged subjects with type 2 diabetes leads to diminished GLP-1 production.

AIMS: Glucagon-like peptide 1 (GLP-1) is produced by the L subtype of enteroendocrine cells (EECs). Patients with type 2 diabetes (T2D) exhibit reduced incretin effect, but the pathophysiology and functional change of the L-cells remain unclear. Deciphering the mechanisms of the biological changes in L-cells under T2D conditions may assist in the research of gut-based strategies for T2D therapy. METHODS: We investigated the fasting serum GLP-1 levels and the distribution of colonic L-cells in young and aged participants with and without T2D. Additionally, we established an aged male T2D Wistar rat model subjected to a long-term high-fat and high-fructose (HFHF) diet. Histological investigations and single-cell RNA sequencing (scRNA-seq) analyses were performed to explore the mechanisms underlying functional changes in the colonic EECs. RESULTS: We observed a decline in circulating GLP-1 levels and a reduced number of colonic L-cells in elderly patients with T2D. The mechanisms underlying impaired L-cell formation and disturbed GLP-1 production were revealed using aged T2D rats induced by a long-term HFHF diet. The scRNA-seq results showed that the transcription factors that regulate L-cell commitment, such as Foxa1, were downregulated, and the expression of genes that participate in encoding GLP-1, GLP-1 posttranslational processing, hormone secretion, and nutrient sensing was disturbed. CONCLUSIONS: Taken together, the reduced L-cell lineage commitment and disturbed L-cell functions might be the major cause of the reduced GLP-1 production in aged populations with T2D. Our study provides new insights for identifying novel targets in colonic L-cells for improving endogenous GLP-1 production.

FOXA1 prolongs S phase and promotes cancer progression in non-small cell lung cancer through upregulation of CDC5L and activation of the ERK1/2 and JAK2 pathways.

Non-small cell lung cancer (NSCLC) causes high mortality worldwide; however, its molecular pathways have not been fully investigated. The relationship between FOXA1 and CDC5L as well as their roles in NSCLC have not been comprehensively studied. Clinical tissues were collected from 78 NSCLC patients for clinical studies. The BEAS-2B human normal lung epithelial cell line and the A549, Calu-3, H526 and H2170 human NSCLC cell lines were used for in vitro studies. sh-FOXA1 and oe-CDC5L constructs were used to generate knockdown and overexpression models, respectively. The CCK-8 assay was used to analyze cell viability. The cell cycle and apoptosis were evaluated by flow cytometry analysis. The relationship between FOXA1 and CDC5L was demonstrated using dual-luciferase and ChIP assays. Gene levels were examined via immunohistochemistry, qRT-PCR and western blot analysis. FOXA1 levels were increased in NSCLC clinical tissues and cell lines. Depletion of FOXA1 increased the apoptosis rate and increased the proportion of cells in G2/M phase. In addition, we demonstrated that FOXA1 was directly bound to the promoter of CDC5L and that depletion of FOXA1 inhibited CDC5L expression. Overexpression of CDC5L induced ERK1/2 phosphorylation, induced JAK2 phosphorylation, inhibited cell apoptosis, prolonged S phase, and significantly reversed the effects of FOXA1 knockdown on the progression of NSCLC. The present study demonstrated that FOXA1 prolongs S phase and promotes NSCLC progression through upregulation of CDC5L and activation of the ERK1/2 and JAK2 pathways.

AGR2 and FOXA1 as prognostic markers in ER-positive breast cancer.

BACKGROUND: The prognostic role of either forkhead box A1 (FOXA1) or anterior gradient 2 (AGR2) in breast cancer has been found separately. Considering that there were interplays between them depending on ER status, we aimed to assess the statistical interaction between AGR2 and FOXA1 on breast cancer prognosis and examine the prognostic role of the combination of them by ER status. METHODS: AGR2 and FOXA1 expression in tumor tissues were evaluated with tissue microarrays by immunohistochemistry in 915 breast cancer patients with follow up data. The expression levels of these two markers were treated as binary variables, and many different cutoff values were tried for each marker. Survival and Cox proportional hazard analyses were used to evaluate the relationship between AGR2, FOXA1 and prognosis, and the statistical interaction between them on the prognosis was assessed on multiplicative scale. RESULTS: Statistical interaction between AGR2 and FOXA1 on the PFS was significant with all the cutoff points in ER-positive breast cancer patients but not ER-negative ones. Among ER-positive patients, the poor prognostic role of the high level of FOXA1 was significant only in patients with the low level of AGR2, and vice versa. When AGR2 and FOXA1 were considered together, patients with low levels of both markers had significantly longer PFS compared with all other groups. CONCLUSIONS: There was a statistical interaction between AGR2 and FOXA1 on the prognosis of ER-positive breast cancer. The combination of AGR2 and FOXA1 was a more useful marker for the prognosis of ER-positive breast cancer patients.

SETD7 functions as a transcription repressor in prostate cancer via methylating FOXA1.

Dysregulation of histone lysine methyltransferases and demethylases is one of the major mechanisms driving the epigenetic reprogramming of transcriptional networks in castration-resistant prostate cancer (CRPC). In addition to their canonical histone targets, some of these factors can modify critical transcription factors, further impacting oncogenic transcription programs. Our recent report demonstrated that LSD1 can demethylate the lysine 270 of FOXA1 in prostate cancer (PCa) cells, leading to the stabilization of FOXA1 chromatin binding. This process enhances the activities of the androgen receptor and other transcription factors that rely on FOXA1 as a pioneer factor. However, the identity of the methyltransferase responsible for FOXA1 methylation and negative regulation of the FOXA1-LSD1 oncogenic axis remains unknown. SETD7 was initially identified as a transcriptional activator through its methylation of histone 3 lysine 4, but its function as a methyltransferase on nonhistone substrates remains poorly understood, particularly in the context of PCa progression. In this study, we reveal that SETD7 primarily acts as a transcriptional repressor in CRPC cells by functioning as the major methyltransferase targeting FOXA1-K270. This methylation disrupts FOXA1-mediated transcription. Consistent with its molecular function, we found that SETD7 confers tumor suppressor activity in PCa cells. Moreover, loss of SETD7 expression is significantly associated with PCa progression and tumor aggressiveness. Overall, our study provides mechanistic insights into the tumor-suppressive and transcriptional repression activities of SETD7 in mediating PCa progression and therapy resistance.

Different chromatin-scanning modes lead to targeting of compacted chromatin by pioneer factors FOXA1 and SOX2.

Pioneer transcription factors interact with nucleosomes to scan silent, compact chromatin, enabling cooperative events that modulate gene activity. While at a subset of sites pioneer factors access chromatin by assisted loading with other transcription factors, the nucleosome-binding properties of pioneer factors enable them to initiate zygotic genome activation, embryonic development, and cellular reprogramming. To better understand nucleosome targeting in vivo, we assess whether pioneer factors FoxA1 and Sox2 target stable or unstable nucleosomes and find that they target DNase-resistant, stable nucleosomes, whereas HNF4A, a non-nucleosome binding factor, targets open, DNase-sensitive chromatin. Despite FOXA1 and SOX2 targeting similar proportions of DNase-resistant chromatin, using single-molecule tracking, we find that FOXA1 uses lower nucleoplasmic diffusion and longer residence times while SOX2 uses higher nucleoplasmic diffusion and shorter residence times to scan compact chromatin, while HNF4 scans compact chromatin much less efficiently. Thus, pioneer factors target compact chromatin through distinct processes.

Lysosome-dependent FOXA1 ubiquitination contributes to luminal lineage of advanced prostate cancer.

Changes in FOXA1 (forkhead box protein A1) protein levels are well associated with prostate cancer (PCa) progression. Unfortunately, direct targeting of FOXA1 in progressive PCa remains challenging due to variations in FOXA1 protein levels, increased FOXA1 mutations at different stages of PCa, and elusive post-translational FOXA1 regulating mechanisms. Here, we show that SKP2 (S-phase kinase-associated protein 2) catalyzes K6- and K29-linked polyubiquitination of FOXA1 for lysosomal-dependent degradation. Our data indicate increased SKP2:FOXA1 protein ratios in stage IV human PCa compared to stages I-III, together with a strong inverse correlation (r = -0.9659) between SKP2 and FOXA1 levels, suggesting that SKP2-FOXA1 protein interactions play a significant role in PCa progression. Prostate tumors of Pten/Trp53 mice displayed increased Skp2-Foxa1-Pcna signaling and colocalization, whereas disruption of the Skp2-Foxa1 interplay in Pten/Trp53/Skp2 triple-null mice demonstrated decreased Pcna levels and increased expression of Foxa1 and luminal positive cells. Treatment of xenograft mice with the SKP2 inhibitor SZL P1-41 decreased tumor proliferation, SKP2:FOXA1 ratios, and colocalization. Thus, our results highlight the significance of the SKP2-FOXA1 interplay on the luminal lineage in PCa and the potential of therapeutically targeting FOXA1 through SKP2 to improve PCa control.

E3 ubiquitin ligase neural precursor cell-expressed developmentally downregulated gene 4 motivates FOXA1 ubiquitination and restrains proliferation of diffuse large B-cell lymphoma cells via the Wnt/ß-Catenin pathway.

Neural precursor cell-expressed developmentally downregulated gene 4 (NEDD4) is an E3 ubiquitin ligase that recognizes substrates via protein-protein interactions and takes part in tumor development. This study aims to clarify NEDD4's functions in diffuse large B-cell lymphoma (DLBCL) and its downstream mechanisms. Collection of 53 DLBCL tissues and adjacent normal lymphoid tissues, and detection of NEDD4 and Forkhead box protein A1 (FOXA1) in the tissues were conducted. The selection of DLBCL cells was for FARAGE, and test of cells' advancement was after transfection. Analysis of NEDD4 and FOXA1's link, and test of Wnt/ß-catenin pathway were implemented. In vivo tumor xenograft experiments were put into effect. Detection of the pathological conditions of tumor tissues and the positive Ki67 in the family was implemented. It came out NEDD4 was reduced in DLBCL tissues and cell lines, and FOXA1 was elevated; Enhancing NEDD4 or repressing FOXA1 refrained DLBCL cells' advancement; NEDD4 could combine with FOXA1 and trigger its ubiquitination and degradation; NEDD4 inactivates the Wnt/ß-catenin pathway by motivating FOXA1 ubiquitination; NEDD4 enhancement refrained DLBCL growth in vivo. In conclusion, the E3 ubiquitin ligase NEDD4 accelerates FOXA1 ubiquitination but refrains DLBCL cell proliferation via the Wnt/ß-Catenin pathway.

LncRNA NKILA Exacerbates Alzheimer's Disease Progression by Regulating the FOXA1-Mediated Transcription of TNFAIP1.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases in the world, which seriously affects AD patients' life quality. Recently, long non-coding RNAs (lncRNAs) have been reported to play a key role in AD pathogenesis, however, the specific mechanism remains unclear. Herein, we aimed to investigate the role of lncRNA NKILA in AD. The learning and memory performance of rats from streptozotocin (STZ)-treated or other treated groups were tested by Morris water maze test. Relative levels of genes and proteins were measured using RT-qPCR and Western blotting. Mitochondrial membrane potential was tested by JC-1 staining. Levels of ROS, SOD, MDA, GSH-Px, and LDH were measured using corresponding commercial kits. Apoptosis was evaluated by TUNEL staining or Flow cytometry assay. RNA Immunoprecipitation (RIP), RNA pulldown, Chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays were utilized to test the interaction between indicated molecules. STZ treatment caused learning and memory impairment in rats and oxidative stress damage in SH-SY5Y cells. LncRNA NKILA was found to be elevated in the hippocampal tissues of rats and SH-SY5Y cells after STZ exposure. Knockdown of lncRNA NKILA alleviated STZ-induced neuronal damage. Furthermore, lncRNA NKILA could bind to ELAVL1, which regulate the stability of FOXA1 mRNA. Moreover, TNFAIP1 transcription process was controlled by FOXA1, which targeted the promoter of TNFAIP1. In vivo results demonstrated that lncRNA NKILA accelerated STZ-induced neuronal damage and oxidative stress by FOXA1/TNFAIP1 axis. Our findings indicated that knockdown of lncRNA NKILA inhibited the neuronal damage and oxidative stress induced by STZ through the FOXA1/TNFAIP1 axis, thereby alleviating the development of AD, revealing a promising therapeutic axis for AD treatment.