Mecp2 fine-tunes quiescence exit by targeting nuclear receptors.

Quiescence (G0) maintenance and exit are crucial for tissue homeostasis and regeneration in mammals. Here, we show that methyl-CpG binding protein 2 (Mecp2) expression is cell cycle-dependent and negatively regulates quiescence exit in cultured cells and in an injury-induced liver regeneration mouse model. Specifically, acute reduction of Mecp2 is required for efficient quiescence exit as deletion of Mecp2 accelerates, while overexpression of Mecp2 delays quiescence exit, and forced expression of Mecp2 after Mecp2 conditional knockout rescues cell cycle reentry. The E3 ligase Nedd4 mediates the ubiquitination and degradation of Mecp2, and thus facilitates quiescence exit. A genome-wide study uncovered the dual role of Mecp2 in preventing quiescence exit by transcriptionally activating metabolic genes while repressing proliferation-associated genes. Particularly disruption of two nuclear receptors, Rara or Nr1h3, accelerates quiescence exit, mimicking the Mecp2 depletion phenotype. Our studies unravel a previously unrecognized role for Mecp2 as an essential regulator of quiescence exit and tissue regeneration.

Functional implications of NHR-210 enrichment in C. elegans cephalic sheath glia: insights into metabolic and mitochondrial disruptions in Parkinson's disease models.

Glial cells constitute nearly half of the mammalian nervous system's cellular composition. The glia in C. elegans perform majority of tasks comparable to those conducted by their mammalian equivalents. The cephalic sheath (CEPsh) glia, which are known to be the counterparts of mammalian astrocytes, are enriched with two nuclear hormone receptors (NHRs)-NHR-210 and NHR-231. This unique enrichment makes the CEPsh glia and these NHRs intriguing subjects of study concerning neuronal health. We endeavored to assess the role of these NHRs in neurodegenerative diseases and related functional processes, using transgenic C. elegans expressing human alpha-synuclein. We employed RNAi-mediated silencing, followed by behavioural, functional, and metabolic profiling in relation to suppression of NHR-210 and 231. Our findings revealed that depleting nhr-210 changes dopamine-associated behaviour and mitochondrial function in human alpha synuclein-expressing strains NL5901 and UA44, through a putative target, pgp-9, a transmembrane transporter. Considering the alteration in mitochondrial function and the involvement of a transmembrane transporter, we performed metabolomics study via HR-MAS NMR spectroscopy. Remarkably, substantial modifications in ATP, betaine, lactate, and glycine levels were seen upon the absence of nhr-210. We also detected considerable changes in metabolic pathways such as phenylalanine, tyrosine, and tryptophan biosynthesis metabolism; glycine, serine, and threonine metabolism; as well as glyoxalate and dicarboxylate metabolism. In conclusion, the deficiency of the nuclear hormone receptor nhr-210 in alpha-synuclein expressing strain of C. elegans, results in altered mitochondrial function, coupled with alterations in vital metabolite levels. These findings underline the functional and physiological importance of nhr-210 enrichment in CEPsh glia.

The Interplay between Endocrine-Disrupting Chemicals and the Epigenome towards Metabolic Dysfunction-Associated Steatotic Liver Disease: A Comprehensive Review.

Metabolic dysfunction-associated steatotic liver disease (MASLD), described as the most prominent cause of chronic liver disease worldwide, has emerged as a significant public health issue, posing a considerable challenge for most countries. Endocrine-disrupting chemicals (EDCs), commonly found in daily use items and foods, are able to interfere with nuclear receptors (NRs) and disturb hormonal signaling and mitochondrial function, leading, among other metabolic disorders, to MASLD. EDCs have also been proposed to cause transgenerationally inherited alterations leading to increased disease susceptibility. In this review, we are focusing on the most prominent linking pathways between EDCs and MASLD, their role in the induction of epigenetic transgenerational inheritance of the disease as well as up-to-date practices aimed at reducing their impact.

A CRM1-dependent nuclear export signal in Autographa californica multiple nucleopolyhedrovirus Ac93 is important for the formation of intranuclear microvesicles.

Autographa californica multiple nucleopolyhedrovirus (AcMNPV) Ac93 is highly conserved in all sequenced baculovirus genomes, and it plays important roles in both the nuclear egress of nucleocapsids and the formation of intranuclear microvesicles. In this study, we characterized a cellular CRM1-dependent nuclear export signal (NES) of AcMNPV Ac93. Bioinformatic analysis revealed that AcMNPV Ac93 may contain an NES at amino acids 115-125. Green fluorescent protein (GFP) fused to the NES (GFP:NES) of AcMNPV Ac93 is localized to the cytoplasm of transfected cells. Multiple point mutation analysis demonstrated that NES is important for the nuclear export of GFP:NES. Bimolecular fluorescence complementation experiments and co-immunoprecipitation assays confirmed that Ac93 interacts with Spodoptera frugiperda CRM1 (SfCRM1). However, AcMNPV Ac34 inhibits cellular CRM1-dependent nuclear export of GFP:NES. To determine whether the NES in AcMNPV Ac93 is important for the formation of intranuclear microvesicles, an ac93-null AcMNPV bacmid was constructed; the wild-type and NES-mutated Ac93 were reinserted into the ac93-null AcMNPV bacmid. Immunofluorescence analysis showed that Ac93 and SfCRM1 were predominantly colocalized at intranuclear microvesicles in infected cells, while the construct containing point mutations at residues 123 and 125 of Ac93 resulted in a defect in budded virus production and the abolishment of intranuclear microvesicles. Together, these data demonstrate that Ac93 contains a functional NES, which is required for the production of progeny viruses and the formation of intranuclear microvesicles.IMPORTANCEAutographa californica multiple nucleopolyhedrovirus (AcMNPV) Ac93 is important for the formation of intranuclear microvesicles. However, how the baculovirus manipulates Ac93 for the formation of intranuclear microvesicles is unclear. In this study, we identified a nuclear export signal (NES) at amino acids 115-125 of AcMNPV Ac93. Our results showed that the NES is required for the interaction between Ac93 and Spodoptera frugiperda CRM1 (SfCRM1). However, AcMNPV Ac34 inhibits the nuclear export of green fluorescent protein fused to the NES. Our analysis revealed that Ac93 and SfCRM1 were predominantly colocalized at intranuclear microvesicles in AcMNPV-infected cells. Together, our results indicate that Ac93 participates in the formation of intranuclear microvesicles via the Ac93 NES-mediated CRM1 pathway.

Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin.

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

Ablation of IFNγ in myeloid cells suppresses liver inflammation and fibrogenesis in mice with hepatic small heterodimer partner (SHP) deletion.

BACKGROUND: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a common complication of obesity and, in severe cases, progresses to metabolic dysfunction-associated steatohepatitis (MASH). Small heterodimer partner (SHP) is an orphan member of the nuclear receptor superfamily and regulates metabolism and inflammation in the liver via a variety of pathways. In this study, we investigate the molecular foundation of MASH progression in mice with hepatic SHP deletion and explore possible therapeutic means to reduce MASH. METHODS: Hepatic SHP knockout mice (SHPΔhep) and their wild-type littermates (SHPfl/fl) of both sexes were fed a fructose diet for 14 weeks and subjected to an oral glucose tolerance test. Then, plasma lipids were determined, and liver lipid metabolism and inflammation pathways were analyzed with immunoblotting, RNAseq, and qPCR assays. To explore possible therapeutic intersections of SHP and inflammatory pathways, SHPΔhep mice were reconstituted with bone marrow lacking interferon γ (IFNγ-/-) to suppress inflammation. RESULTS: Hepatic deletion of SHP in mice fed a fructose diet decreased liver fat and increased proteins for fatty acid oxidation and liver lipid uptake, including UCP1, CPT1α, ACDAM, and SRBI. Despite lower liver fat, hepatic SHP deletion increased liver inflammatory F4/80+ cells and mRNA levels of inflammatory cytokines (IL-12, IL-6, Ccl2, and IFNγ) in both sexes and elevated endoplasmic reticulum stress markers of Cox2 and CHOP in female mice. Liver bulk RNAseq data showed upregulation of genes whose protein products regulate lipid transport, fatty acid oxidation, and inflammation in SHPΔhep mice. The increased inflammation and fibrosis in SHPΔhep mice were corrected with bone marrow-derived IFNγ-/- myeloid cell transplantation. CONCLUSION: Hepatic deletion of SHP improves fatty liver but worsens hepatic inflammation possibly by driving excess fatty acid oxidation, which is corrected by deletion of IFNγ specifically in myeloid cells. This suggests that hepatic SHP limits fatty acid oxidation during fructose diet feeding but, in doing so, prevents pro-MASH pathways. The IFNγ-mediated inflammation in myeloid cells appears to be a potential therapeutic target to suppress MASH.

Increased hepatoprotective effects of the novel farnesoid X receptor agonist INT-787 versus obeticholic acid in a mouse model of nonalcoholic steatohepatitis.

The nuclear farnesoid X receptor (FXR), a master regulator of bile acid and metabolic homeostasis, is a key target for treatment of nonalcoholic steatohepatitis (NASH). This study compared efficacy of FXR agonists obeticholic acid (OCA) and INT-787 by liver histopathology, plasma biomarkers of liver damage, and hepatic gene expression profiles in the Amylin liver NASH (AMLN) diet-induced and biopsy-confirmed Lepob/ob mouse model of NASH. Lepob/ob mice were fed the AMLN diet for 12 weeks before liver biopsy and subsequent treatment with vehicle, OCA, or INT-787 for 8 weeks. Hepatic steatosis, inflammation, and fibrosis (liver lipids, galectin-3, and collagen 1a1 [Col1a1], respectively), as well as plasma alanine transaminase (ALT) and aspartate transaminase (AST) levels, were assessed. Hepatic gene expression was assessed in Lepob/ob mice that were fed the AMLN diet for 14 weeks then treated with vehicle, OCA, or INT-787 for 2 weeks. INT-787, which is equipotent to OCA but more hydrophilic, significantly reduced liver lipids, galectin-3, and Col1a1 compared with vehicle, and to a greater extent than OCA. INT-787 significantly reduced plasma ALT and AST levels, whereas OCA did not. INT-787 modulated a substantially greater number of genes associated with FXR signaling, lipid metabolism, and stellate cell activation relative to OCA in hepatic tissue. These findings demonstrate greater efficacy of INT-787 treatment compared with OCA in improving liver histopathology, decreasing liver enzyme levels, and enhancing gene regulation, suggesting superior clinical potential of INT-787 for the treatment of NASH and other chronic liver diseases.

Natural Products in the Modulation of Farnesoid X Receptor Against Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is a global health concern with a high prevalence and increasing economic burden, but official medicine remains unavailable. Farnesoid X receptor (FXR), a nuclear receptor member, is one of the most promising drug targets for NAFLD therapy that plays a crucial role in modulating bile acid, glucose, and lipid homeostasis, as well as inhibits hepatic inflammation and fibrosis. However, the rejection of the FXR agonist, obecholic acid, by the Food and Drug Administration for treating hepatic fibrosis raises a question about the functions of FXR in NAFLD progression and the therapeutic strategy to be used. Natural products, such as FXR modulators, have become the focus of attention for NAFLD therapy with fewer adverse reactions. The anti-NAFLD mechanisms seem to act as FXR agonists and antagonists or are involved in the FXR signaling pathway activation, indicating a promising target of FXR therapeutic prospects using natural products. This review discusses the effective mechanisms of FXR in NAFLD alleviation, and summarizes currently available natural products such as silymarin, glycyrrhizin, cycloastragenol, berberine, and gypenosides, for targeting FXR, which can facilitate development of naturally targeted drug by medicinal specialists for effective treatment of NAFLD.

Aspirin Caused Intestinal Damage through FXR and ET-1 Signaling Pathways.

Aspirin is a non-steroidal, anti-inflammatory drug often used long term. However, long-term or large doses will cause gastrointestinal adverse reactions. To explore the mechanism of intestinal damage, we used non-targeted metabolomics; farnesoid X receptor (FXR) knockout mice, which were compared with wild-type mice; FXR agonists obeticholic acid (OCA) and chenodeoxycholic acid (CDCA); and endothelin-producing inhibitor estradiol to explore the mechanisms of acute and chronic intestinal injuries induced by aspirin from the perspective of molecular biology. Changes were found in the bile acids taurocholate acid (TCA) and tauro-ß-muricholic acid (T-ß-MCA) in the duodenum, and we detected a significant inhibition of FXR target genes. After additional administration of the FXR agonists OCA and CDCA, duodenal villus damage and inflammation were effectively improved. The results in the FXR knockout mice and wild-type mice showed that the overexpression of endothelin 1 (ET-1) was independent of FXR regulation after aspirin exposure, whereas CDCA was able to restore the activation of ET-1, which was induced by aspirin in wild-type mice in an FXR-dependent manner. The inhibition of ET-1 production could also effectively protect against small bowel damage. Therefore, the study revealed the key roles of the FXR and ET-1 pathways in acute and chronic aspirin-induced intestinal injuries, as well as strategies on alleviating aspirin-induced gastrointestinal injury by activating FXR and inhibiting ET-1 overexpression.

Ecdysone-controlled nuclear receptor ERR regulates metabolic homeostasis in the disease vector mosquito Aedes aegypti.

Hematophagous mosquitoes require vertebrate blood for their reproductive cycles, making them effective vectors for transmitting dangerous human diseases. Thus, high-intensity metabolism is needed to support reproductive events of female mosquitoes. However, the regulatory mechanism linking metabolism and reproduction in mosquitoes remains largely unclear. In this study, we found that the expression of estrogen-related receptor (ERR), a nuclear receptor, is activated by the direct binding of 20-hydroxyecdysone (20E) and ecdysone receptor (EcR) to the ecdysone response element (EcRE) in the ERR promoter region during the gonadotropic cycle of Aedes aegypti (named AaERR). RNA interference (RNAi) of AaERR in female mosquitoes led to delayed development of ovaries. mRNA abundance of genes encoding key enzymes involved in carbohydrate metabolism (CM)-glucose-6-phosphate isomerase (GPI) and pyruvate kinase (PYK)-was significantly decreased in AaERR knockdown mosquitoes, while the levels of metabolites, such as glycogen, glucose, and trehalose, were elevated. The expression of fatty acid synthase (FAS) was notably downregulated, and lipid accumulation was reduced in response to AaERR depletion. Dual luciferase reporter assays and electrophoretic mobility shift assays (EMSA) determined that AaERR directly activated the expression of metabolic genes, such as GPI, PYK, and FAS, by binding to the corresponding AaERR-responsive motif in the promoter region of these genes. Our results have revealed an important role of AaERR in the regulation of metabolism during mosquito reproduction and offer a novel target for mosquito control.

Nr5a2 ensures inner cell mass formation in mouse blastocyst.

Recent studies have elucidated Nr5a2's role in activating zygotic genes during early mouse embryonic development. Subsequent research, however, reveals that Nr5a2 is not critical for zygotic genome activation but is vital for the gene program between the 4- and 8-cell stages. A significant gap exists in experimental evidence regarding its function during the first lineage differentiation's pivotal period. In this study, we observed that approximately 20% of embryos developed to the blastocyst stage following Nr5a2 ablation. However, these blastocysts lacked inner cell mass (ICM), highlighting Nr5a2's importance in first lineage differentiation. Mechanistically, using RNA sequencing and CUT&Tag, we found that Nr5a2 transcriptionally regulates ICM-specific genes, such as Oct4, to establish the pluripotent network. Interference with or overexpression of Nr5a2 in single blastomeres of 2-cell embryos can alter the fate of daughter cells. Our results indicate that Nr5a2 works as a doorkeeper to ensure ICM formation in mouse blastocyst.

The spectrum of neurological presentation in individuals affected by TBL1XR1 gene defects.

BACKGROUND: TBL1XR1 encodes a F-box-like/WD40 repeat-containing protein that plays a role in transcription mediated by nuclear receptors and is a known genetic cause of neurodevelopmental disease of childhood (OMIM# 608628). Yet the developmental trajectory and progression of neurologic symptoms over time remains poorly understood. METHODS: We developed and distributed a survey to two closed Facebook groups devoted to families of patients with TBL1XR1-related disorder. The survey consisted of 14 subsections focused upon the developmental trajectories of cognitive, behavioral, motor, and other neurological abnormalities. Data were collected and managed using REDCap electronic data capture tools. RESULTS: Caregivers of 41 patients with a TBL1XR1-related disorder completed the cross-sectional survey. All reported variants affecting a single amino acid, including missense mutations and in-frame deletions, were found in the WD40 repeat regions of Tbl1xr1. These are domains considered important for protein-protein interactions that may plausibly underlie disease pathology. The majority of patients were diagnosed with a neurologic condition before they received their genetic diagnosis. Language appeared most significantly affected with only a minority of the cohort achieving more advanced milestones in this domain. CONCLUSION: TBL1XR1-related disorder encompasses a spectrum of clinical presentations, marked by early developmental delay ranging in severity, with a subset of patients experiencing developmental regression in later childhood.

MicroRNA-34c-5p Reduces Malignant Properties of Lung Cancer Cells through Regulation of TBL1XR1/Wnt/ß-catenin Signaling.

INTRODUCTION: Lung cancer is common cancer with high mortality. A growing number of studies have focused on investigating the regulatory effects of microRNAs (miRs/miRNAs) during cancer progression. Nevertheless, the biological function of miR- 34c-5p in lung cancer and the underlying mechanism have not been determined. This study explored the effect of miR-34c-5p on the malignant behaviors of lung cancer cells. METHODS: In this study, we utilized diverse public databases to obtain differentially expressed miRNAs. Then, qRT-PCR and western blot were conducted to determine miR-34c-5p and transducin ß-like 1 X-linked receptor 1 (TBL1XR1) expression. Next, H1299 and H460 cells were transfected with miR-34c-5p-mimic and pcDNA3.1- TBL1XR1. To examine the anticancer effects of miR-34c-5p, CCK-8, scratch, and Matrigel-Transwell assays were conducted to test cell viability, migration, and invasion, respectively. The StarBase database and dual-luciferase reporter gene assay were used to predict and verify the relationship between miR-34c-5p and TBL1XR1. RESULTS: Finally, Wnt/ß-catenin signaling- and epithelial-mesenchymal transition (EMT)- related protein levels were detected using western blot. The results demonstrated that miR-34c-5p was poorly expressed in lung cancer cells, while TBL1XR1 was highly expressed. The findings also confirmed the direct interaction between miR-34c-5p and TBL1XR1. In H1299 and H460 cells, miR-34c-5p overexpression inhibited cell proliferation, migration, and invasion, Wnt/ß-catenin signaling activity, and EMT, while TBL1XR1 upregulation reversed these effects of miR-34c-5p overexpression. CONCLUSION: These findings illustrated that miR-34c-5p might repress the malignant behaviors of lung cancer cells via TBL1XR1, providing evidence for miR-34c-5p-based lung cancer therapy.

Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy.

Systemic modalities are crucial in the management of disseminated malignancies and liquid tumours. However, patient responses and tolerability to treatment are generally poor and those that enter remission often return with refractory disease. Combination therapies provide a methodology to overcome chemoresistance mechanisms and address dose-limiting toxicities. A deeper understanding of tumorigenic processes at the molecular level has brought a targeted therapy approach to the forefront of cancer research, and novel cancer biomarkers are being identified at a rapid rate, with some showing potential therapeutic benefits. The Karyopherin superfamily of proteins is soluble receptors that mediate nucleocytoplasmic shuttling of proteins and RNAs, and recently, nuclear transport receptors have been recognized as novel anticancer targets. Inhibitors against nuclear export have been approved for clinical use against certain cancer types, whereas inhibitors against nuclear import are in preclinical stages of investigation. Mechanistically, targeting nucleocytoplasmic shuttling has shown to abrogate oncogenic signalling and restore tumour suppressor functions through nuclear sequestration of relevant proteins and mRNAs. Hence, nuclear transport inhibitors display broad spectrum anticancer activity and harbour potential to engage in synergistic interactions with a wide array of cytotoxic agents and other targeted agents. This review is focussed on the most researched nuclear transport receptors in the context of cancer, XPO1 and KPNB1, and highlights how inhibitors targeting these receptors can enhance the therapeutic efficacy of standard of care therapies and novel targeted agents in a combination therapy approach. Furthermore, an updated review on the therapeutic targeting of lesser characterized karyopherin proteins is provided and resistance to clinically approved nuclear export inhibitors is discussed.

Knockout of nuclear receptor HR38 gene impairs pupal-adult development in silkworm Bombyx mori.

Nuclear receptors are ligand-regulated transcription factors that play important role in regulating insect metamorphosis through the ecdysone signalling pathway. In this study, we investigated the nuclear receptor HR38 gene in Bombyx mori (BmHR38), belonging to the NR4A subfamily. BmHR38 mRNA was highly expressed in the head and epidermis at the pupal stage. The expression of the BmHR38 gene was influenced by different doses of 20E at different times. A BmHR38 deletion mutant silkworm was generated using the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas9 system. Compared with the wild-type B. mori, the BmHR38 deletion mutant resulted in abnormal development during the pupal stage, leading to either failed eclosion or the formation of abnormal adult wings. After silencing of BmHR38 in the pupal stage, the phenotype of pupa or moth had no significant change, but it did result in reduced egg production. The mRNA levels of USP, E75 and E74 were significantly increased, while the transcript levels of FTZ-F1 were suppressed after RNA interference. Furthermore, interference with BmHR38 also inhibited the expressions of chitin metabolism genes, including Chs1, Chs2, Chi, Chi-h and CDA. Our results suggest that BmHR38 is essential for pupal development and pupa-adult metamorphosis in B. mori by regulating the expression of NRs and chitin metabolism genes.

Let-7a-5p abrogates progression of papillary thyroid carcinoma cells by decreasing nuclear receptor subfamily 6 group a member 1-mediated lipogenesis.

Increasing evidence shows that microRNAs (miRNAs) contribute vital roles in papillary thyroid carcinoma (PTC) carcinogenesis, proliferation, invasion, and so on. As the most common endocrine malignancy, there still have largely unknown molecular events. First, our analysis and open access database information indicates that the downregulation of let-7a-5p accelerates PTC progression. Next, lentivirus mediates the overexpression of let-7a-5p PTC cells, and found let-7a-5p suppressed cancer cells proliferation and invasion. Interestingly, bioinformatics analysis hints NR6A1 is the potential target gene of let-7a-5p. The regulation was validated by luciferase and quantitative reverse transcription polymerase chain reaction (qRT-PCR) in PTC tissue and the clinic tumors. Moreover, let-7a-5p regulated NR6A1 involved in PTC cells lipogensis in vitro and in vivo. Finally, let-7a-5p abrogates PCT xenograft tumors growth, NR6A1 expression and lipogenesis. Taken together, our data indicates that let-7a-5p suppresses PCT progression through decreased lipogenesis, the related let-7a-5p/NR6A1axis might be promising candidate targets for PTC treatment.

XPO1 Enables Adaptive Regulation of mRNA Export Required for Genotoxic Stress Tolerance in Cancer Cells.

Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors. We uncovered here that XPO1 overexpression increases tolerance to genotoxic stress, leading to a poor response to chemoimmunotherapy. Upon DNA damage induced by MYC expression or exogenous compounds, XPO1 bound and exported EIF4E and THOC4 carrying DNA damage repair mRNAs, thereby increasing synthesis of DNA damage repair proteins under conditions of increased turnover. Consequently, XPO1 inhibition decreased the capacity of lymphoma cells to repair DNA damage and ultimately resulted in increased cytotoxicity. In a phase I clinical trial conducted in R/R DLBCL, the combination of selinexor with second-line chemoimmunotherapy was tolerated with early indication of efficacy. Overall, this study reveals that XPO1 overexpression plays a critical role in the increased tolerance of cancer cells to DNA damage while providing new insights to optimize the clinical development of XPO1 inhibitors. SIGNIFICANCE: XPO1 regulates the dynamic ribonucleoprotein nuclear export in response to genotoxic stress to support tolerance and can be targeted to enhance the sensitivity of cancer cells to endogenous and exogenous DNA damage. See related commentary by Knittel and Reinhardt, p. 3.

FXR controls insulin content by regulating Foxa2-mediated insulin transcription.

Farnesoid X receptor (FXR) is a nuclear ligand-activated receptor of bile acids that plays a role in the modulation of insulin content. However, the underlying molecular mechanisms remain unclear. Forkhead box a2 (Foxa2) is an important nuclear transcription factor in pancreatic ß-cells and is involved in ß-cell function. We aimed to explore the signaling mechanism downstream of FXR to regulate insulin content and underscore its association with Foxa2 and insulin gene (Ins) transcription. All experiments were conducted on FXR transgenic mice, INS-1 823/13 cells, and diabetic Goto-Kakizaki (GK) rats undergoing sham or Roux-en-Y gastric bypass (RYGB) surgery. Islets from FXR knockout mice and INS-1823/13 cells with FXR knockdown exhibited substantially lower insulin levels than that of controls. This was accompanied by decreased Foxa2 expression and Ins transcription. Conversely, FXR overexpression increased insulin content, concomitant with enhanced Foxa2 expression and Ins transcription in INS-1 823/13 cells. Moreover, FXR knockdown reduced FXR recruitment and H3K27 trimethylation in the Foxa2 promoter. Importantly, Foxa2 overexpression abrogated the adverse effects of FXR knockdown on Ins transcription and insulin content in INS-1 823/13 cells. Notably, RYGB surgery led to improved insulin content in diabetic GK rats, which was accompanied by upregulated FXR and Foxa2 expression and Ins transcription. Collectively, these data suggest that Foxa2 serves as the target gene of FXR in ß-cells and mediates FXR-enhanced Ins transcription. Additionally, the upregulated FXR/Foxa2 signaling cascade could contribute to the enhanced insulin content in diabetic GK rats after RYGB.

lncRNA799/TBL1XR1/ZEB1 Axis Forms a Feedback Loop to Promote the Epithelial-Mesenchymal Transition of Cervical Cancer Cells.

Cervical cancer is a common malignancy among women worldwide. Long non-coding RNAs (lncRNAs) are frequently involved in the pathogenesis of cervical cancer. Therefore, the present study aimed to investigate the potentials of lncRNA799 in cervical cancer. mRNA and protein expression were detected by reverse transcription-quantitative polymerase chain reaction and Western blot analysis, respectively. Cellular functions were assessed using CCK-8, wound healing and transwell analysis. The binding potential of zinc finger E-box-binding homeobox 1 (ZEB1) on the promoter of lncRNA799 was predicted utilizing the JASPAR database, and was then verified by luciferase and chromatin immunoprecipitation (ChIP) assays. Furthermore, the gene interactions were assessed using RNA immunoprecipitation and co-immunoprecipitation assays. The results demonstrated that lncRNA799 was upregulated in cervical cancer cells. However, lncRNA799 deficiency suppressed the proliferation and epithelial-mesenchymal transition of cervical cancer cells. Furthermore, lncRNA799 could interact with eukaryotic translation initiation factor 4A3 to maintain the mRNA stability of transducin (ß)-like 1 X-linked receptor 1 (TBL1XR1) and promote the interaction between ZEB1 and TBL1XR1. Additionally, the results showed that ZEB1 could transcriptionally activate lncRNA799. Taken together, the present study suggested that the lncRNA799/TBL1XR1/ZEB1 axis could form a positive feedback loop in cervical cancer and could be, therefore, considered as a potential therapeutic strategy for cervical cancer.