BACKGROUND: Recurrent or metastatic cervical cancer have an extremely low 5-year survival rates about 17% due to limited therapeutic options. CDYL plays a critical role in multiple cancer development, as an oncogene or tumor suppressor in a context-dependent manner. However, the role of CDYL in cervical carcinogenesis has not yet been explored.
METHODS: CDYL expression was examined in cervical cancer and cell lines. The effect of CDYL/IRF2BP2/PD-L1 axis on malignant phenotypes of cervical cancer cells were tested with gain-of-function experiments. A mouse model of cervical cancer was developed to validate the in vitro results.
RESULTS: Clinical data analysis revealed that CDYL was downregulated and associated with a poor prognosis in cervical cancer patients. CDYL overexpression suppressed cervical cancer cells proliferation and invasion in vitro and vivo assays and enhanced the immune response by decreasing PD-L1 expression and reversing the tumor immunosuppressing microenvironment. Mechanistically, CDYL inhibited the PD-L1 expression through transcriptionally suppressing IRF2BP2 in cervical cancer cells.
CONCLUSIONS: Taken together, our findings established the crucial role of CDYL in cervical carcinogenesis and sensitivity for immune checkpoint blockade therapy, and supported the hypothesis that CDYL could be a potential novel immunotherapy response predictive biomarker for cervical cancer patients.

BACKGROUND: Super-enhancers (SEs) typically govern the expression of critical oncogenes and play a fundamental role in the initiation and progression of cancer. Focusing on genes that are abnormally regulated by SE in cancer may be a new strategy for understanding pathogenesis. In the context of this investigation, we have identified a previously unreported SE-driven gene IRF2BP2 in neuroblastoma (NB).
METHODS: The expression and prognostic value of IRF2BP2 were detected in public databases and clinical samples. The effect of IRF2BP2 on NB cell growth and apoptosis was evaluated through in vivo and in vitro functional loss experiments. The molecular mechanism of IRF2BP2 was investigated by the study of chromatin regulatory regions and transcriptome sequencing.
RESULTS: The sustained high expression of IRF2BP2 results from the activation of a novel SE established by NB master transcription factors MYCN, MEIS2 and HAND2, and they form a new complex that regulates the gene network associated with the proliferation of NB cell populations. We also observed a significant enrichment of the AP-1 family at the binding sites of IRF2BP2. Remarkably, within NB cells, AP-1 plays a pivotal role in shaping the chromatin accessibility landscape, thereby exposing the binding site for IRF2BP2. This orchestrated action enables AP-1 and IRF2BP2 to collaboratively stimulate the expression of the NB susceptibility gene ALK, thereby upholding the highly proliferative phenotype characteristic of NB.
CONCLUSIONS: Our findings indicate that SE-driven IRF2BP2 can bind to AP-1 to maintain the survival of tumor cells via regulating chromatin accessibility of NB susceptibility gene ALK.

Lymph node metastasis (LNM) is a major determinant for the poor outcome of oral squamous cell carcinoma (OSCC). Interferon regulatory factor 2 binding protein 2 (IRF2BP2) has been reported to modulate the development and progression of several types of cancers, while its role in OSCC with LNM has not been reported yet. The expression of IRF2BP2 and its association with LNM were evaluated by immunohistochemistry and qualitative reverse transcription polymerase chain reaction in clinically collected OSCC tissues. Then, loss-of-function and rescue assays were conducted to identify the role of IRF2BP2-mediated fatty acid oxidation (FAO) in the invasion, lymphoinvasion, and epithelial-mesenchymal transition (EMT) in OSCC cells. Importantly, confocal microscope, transmission electron microscope, immunofluorescence, and Western blot were applied to identify the involvement of mitochondrial fission in IRF2BP2-regulated FAO. Lastly, the in vivo models were established to evaluate the role of IRF2BP2 in OSCC. IRF2BP2 overexpression has been associated with LNM in OSCC, whose knockdown inhibited invasion, lymphoinvasion, and EMT of OSCC cells, as well as retarded FAO rate with CPT1A downregulation. And CPT1A overexpression rescued invasion, lymphoinvasion, and induced EMT in IRF2BP2-silenced OSCC cells. Mechanically, IRF2BP2 accelerated mitochondrial fission by contributing to Drp1 S616 phosphorylation and mitochondrial localization, resulting in the upregulation of CPT1A. In addition, IRF2BP2 knockdown significantly inhibited tumor growth and LNM in vivo. The highly expressed IRF2BP2 may induce the phosphorylation and mitochondrial translocation of Drp1 to activate mitochondrial fission, which upregulated CPT1A expression and FAO rate, resulting in LNM in OSCC. This highlighted a potential therapeutic vulnerability for the treatment of LNM+ OSCC via targeting IRF2BP2-FAO.

Inborn errors of immunity (IEI) are a heterogeneous group of disorders characterized by increased risk of infections, autoimmunity, autoinflammatory diseases, malignancy and allergy. Next-generation sequencing has revolutionized the identification of genetic background of these patients and assists in diagnosis and treatment. In this study, we identified a probable unique monogenic cause of IEI, and evaluated the immunological methods and pathogenic detections.
A family with a member with a clinical diagnosis of IEI was screened by whole genomic sequencing (WGS). Demographic data, clinical manifestations, medical history, physical examination, laboratory findings and imaging features of the patient were extracted from medical records. Comprehensive immune monitoring methods include a complete blood count with differential, serum levels of cytokines and autoantibodies, T-cell and B-cell subsets analysis and measurement of serum immunoglobulins. In addition, metagenomic sequencing (mNGS) of blood, cerebrospinal fluid and biopsy from small intestine were used to detect potential pathogens.
The patient manifested with recurrent infections and autoimmune disorders, who was eventually diagnosed with IEI. Repetitive mNGS tests of blood, cerebrospinal fluid and biopsy from small intestine didn\'t detect pathogenic microorganism. Immunological tests showed a slightly decreased level of IgG than normal, elevated levels of tumor necrosis factor and interleukin-6. Lymphocyte flow cytometry showed elevated total B cells and natural killer cells, decreased total T cells and B-cell plasmablasts. WGS of the patient identified a novel heterozygous mutation in IRF2BP2 (c.439_450dup p. Thr147_Pro150dup), which was also confirmed in his father. The mutation was classified as variant of uncertain significance (VUS) according to the American College of Medical Genetics and Genomics guidelines.
We identified a novel IRF2BP2 mutation in a family with a member diagnosed with IEI. Immune monitoring and WGS as auxiliary tests are helpful in identifying genetic defects and assisting diagnosis in patients with clinically highly suspected immune abnormalities and deficiencies in inflammation regulation. In addition, mNGS techniques allow a more comprehensive assessment of the pathogenic characteristics of these patients. This report further validates the association of IRF2BP2 deficiency and IEI, and expands IEI phenotypes.

BACKGROUND: Ischemic stroke is a very dangerous disease with high incidence, fatality and disability rate in human beings. Massive evidence has indicated that oxidative stress and inflammation are intimately correlated with progression of ischemic stroke. Additionally, LncRNAs were reported to be involved in ischemic stroke. Here, we aim to explore the effects and molecular mechanism of lncRNA OIP5-AS1 on oxidative stress and inflammation in ischemic stroke.
METHODS: HMC3 and SH-SY5Y cells were under the condition of oxygen-glucose deprivation/reoxygenation (OGD/R) treatment to establish cell models of ischemic stroke. Commercial kits were employed to detect the indicators of oxidative stress including ROS, MDA and SOD. The expression of OIP5-AS1, miR-155-5p and IRF2BP2 mRNA was determined using RT-qPCR. The protein levels of inflammatory factors including TNF-α, IL-1β and IL-6 and IRF2BP2 were assessed by western blot and/or ELISA. Luciferase activity assay was employed to validate their correlations among OIP5-AS1, miR-155-5p and IRF2BP2.
RESULTS: In OGD/R-induced HMC3 and SH-SY5Y cells, the expression of OIP5-AS1 and IRF2BP2 was reduced while miR-155-5p was elevated. OGD/R induction promoted oxidative stress and inflammatory response in HMC3 and SH-SY5Y cells, while OIP5-AS1 or IRF2BP2 sufficiency as well as miR-155-5p inhibitor attenuated OGD/R-induced these influences. In addition, IRF2BP2 knockdown abolished the suppressive impacts of OIP5-AS1 overexpression on oxidative stress and inflammatory response in OGD/R-induced HMC3 and SH-SY5Y cells. Mechanistically, OIP5-AS1 enhanced IRF2BP2 expression via sponging miR-155-5p.
CONCLUSIONS: OIP5-AS1 suppressed oxidative stress and inflammatory response to alleviate cell injury caused by OGD/R induction in HMC3 and SH-SY5Y cells through regulating miR-155-5p/IRF2BP2 axis, which might offer novel targeted molecules for ischemic stroke therapy.

Thyroid carcinoma (THCA) is a common malignancy of the endocrine system. Further understanding of the molecular mechanism underlying THCA is crucial to develop effective diagnostic therapy and improve its treatments. In this study, we intended to provide novel direction for THCA targeted therapy from the aspect of lncRNA-miRNA-mRNA interaction. We aimed to investigate the function and molecular mechanism of lncRNA ATP1A1-AS1 in THCA.
Gene expression was assessed by reverse transcription quantitative polymerase chain reaction (RT-qPCR). Cell growth was detected by CCK-8 and EdU assays. Flow cytometry was applied for analyzing cell apoptosis. The binding of ATP1A1-AS1 or IRF2BP2 to miR-620 was validated by RNA pulldown and luciferase reporter assays. The protein levels were examined by western blotting.
ATP1A1-AS1 was decreased in THCA cells and tissues. ATP1A1-AS1 overexpression attenuated cell growth and promoted apoptosis. MiR-620, which was upregulated in THCA, was identified as a direct target of ATP1A1-AS1. Furthermore, IRF2BP2 was discovered to be a target of miR-620, which displayed low expression in THCA cells and tissues. Importantly, IRF2BP2 knockdown reversed the influence of ATP1A1-AS1 overexpression on THCA cell proliferation and apoptosis.
LncRNA ATP1A1-AS1 inhibited cell growth and promotes apoptosis in THCA via the miR-620/IRF2BP2 axis.

Cardiomyopathy commonly occurs after sepsis and is closely associated with high mortality in clinic. Interferon regulatory factor-2 binding protein 2 (IRF2BP2) has been identified as a negative regulator of inflammation, but its role in septic cardiomyopathy is unknown. The current study aims to illuminate the regulatory function of IRF2BP2 on sepsis-induced cardiomyopathy and to explore the underlying mechanisms. Protein expression of IRF2BP2 in response to sepsis-induced cardiomyopathy was examined in the heart of mice challenged by LPS intraperitoneal injection. AAV9-delivered IRF2BP2 overexpression in the heart was applied to evaluate the regulatory role of IRF2BP2 in sepsis-induced myocardial depression, inflammatory response, and cell death. The molecular mechanisms underlying IRF2BP2-regulated cardiomyopathy were explored using western blot screening assay. Primary cardiomyocytes have been isolated to further confirm the role and mechanism of IRF2BP2 during septic cardiomyopathy. IRF2BP2 expression was dramatically increased in the heart of mice after LPS administration. AAV9-mediated IRF2BP2 overexpression significantly improved sepsis-induced cardiac dysfunction, inhibited inflammatory cell infiltration and cytokine production, and blocked cell death after LPS treatment. Mechanistically, IRF2BP2 activated AMPK signaling in cardiomyocytes, while inhibiting AMPK activation largely reversed IRF2BP2-benefited inflammatory suppression and cell survival. These findings clearly demonstrated that IRF2BP2 is a potent suppressor of sepsis-induced myocardial depression and related heart impairment. Targeting IRF2BP2 represents a promising therapeutic strategy for septic cardiomyopathy.

Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional repressor involved in regulating gene expression and other biological processes, including tumorigenesis. However, the clinical significance and roles of IRF2BP2 in human gastric cancer (GC) remain uncertain. Clinical GC tissues were obtained from GC patients at the First Affiliated Hospital of Nanchang University. Immunohistochemistry (IHC) was conducted to detect the IRF2BP2 protein in clinical paraffin specimens. Cell proliferation, migration and invasion were evaluated by MTT, colony formation assays and transwell assays. Co-immunoprecipitation was conducted to detect the interaction between TEA domain family members 4 (TEAD4) and vestigial-like family member 4 (VGLL4) or Yes-associated protein 1 (YAP1). Dual-luciferase reporter assay was used to confirm the binding of miR-101-3p to the 3\'-UTR. The expression of IRF2BP2 was significantly higher in GC tissues than in normal tissues. Patients with higher IRF2BP2 protein expression had lower survival. IRF2BP2 knockdown inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in GC cells. IRF2BP2 knockdown decreased the mRNA and protein levels of connective tissue growth factor (CTGF). The interaction between IRF2BP2 and VGLL4 increased the binding of TEAD4 to YAP1, resulting in the transcriptional coactivation of CTGF. In addition, miR-101-3p suppressed the expression of CTGF by directly targeting the 3\'-UTR of IRF2BP2. Taken together, these findings provide a model for the role of miR-101-3p-IRF2BP2-CTGF signalling axis in GC and a novel insight into the mechanism of GC progression and metastasis.

Hypoxia is widely considered as a limiting factor in vertebrate embryonic development, which requires adequate oxygen delivery for efficient energy metabolism, while nowadays some researches have revealed that hypoxia can induce stem cells so as to improve embryonic development. Erythroid differentiation is the oxygen delivery method employed by vertebrates at the very early step of embryo development, however, the mechanism how erythroid progenitor cell was triggered into mature erythrocyte is still not clear. In this study, after detecting the upregulation of vgll4b in response to oxygen levels, we generated vgll4b mutant zebrafish using CRISPR/Cas9, and verified the resulting impaired heme and dysfunctional erythroid terminal differentiation phenotype. Neither the vgll4b-deficient nor the γ-secretase inhibitor IX (DAPT)-adapted zebrafish were able to mediate HIF1α-induced heme generation. In addition, we showed that vgll4b mutant zebrafish were associated with an impaired erythroid phenotype, induced by the downregulation of alas2, which could be rescued by irf2bp2 depletion. Further mechanistic studies revealed that zebrafish VGLL4 sequesters IRF2BP2, thereby inhibiting its repression of alas2 expression and heme biosynthesis. These processes occur primarily via the VGLL4 TDU1 and IRF2BP2 ring finger domains. Our study also indicates that VGLL4 is a key player in the mediation of NOTCH1-dependent HIF1α-regulated erythropoiesis and can be sensitively regulated by oxygen concentrations. On the other hand, VGLL4 is a pivotal regulator of heme biosynthesis and erythroid terminal differentiation, which collectively improve oxygen metabolism.

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