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Journal of Experimental & Clinical... Sep 2023FAT4 (FAT Atypical Cadherin 4) is a member of the cadherin-associated protein family, which has been shown to function as a tumor suppressor by inhibiting proliferation...
BACKGROUND
FAT4 (FAT Atypical Cadherin 4) is a member of the cadherin-associated protein family, which has been shown to function as a tumor suppressor by inhibiting proliferation and metastasis. The Wnt/β-catenin pathway activation is highly associated with PD-L1-associated tumor immune escape. Here, we report the mechanism by which FAT4 overexpression regulates anti-tumor immunity in cervical cancer by inhibiting PD-L1 N-glycosylation and cell membrane localization in a β-catenin-dependent manner.
METHODS
FAT4 expression was first detected in cervical cancer tissues and cell lines. Cell proliferation, clone formation, and immunofluorescence were used to determine the tumor suppressive impact of FAT4 overexpression in vitro, and the findings were confirmed in immunodeficient and immunocomplete mice xenografts. Through functional and mechanistic experiments in vivo and in vitro, we investigated how FAT4 overexpression affects the antitumor immunity via the β-catenin/STT3/PD-L1 axis.
RESULTS
FAT4 is downregulated in cervical cancer tissues and cell lines. We determined that FAT4 binds to β-catenin and antagonizes its nuclear localization, promotes phosphorylation and degradation of β-catenin by the degradation complexes (AXIN1, APC, GSK3β, CK1). FAT4 overexpression decreases programmed death-ligand 1 (PD-L1) mRNA expression at the transcriptional level, and causes aberrant glycosylation of PD-L1 via STT3A at the post-translational modifications (PTMs) level, leading to its endoplasmic reticulum (ER) accumulation and polyubiquitination-dependent degradation. We found that FAT4 overexpression promotes aberrant PD-L1 glycosylation and degradation in a β-catenin-dependent manner, thereby increasing cytotoxic T lymphocyte (CTL) activity in immunoreactive mouse models.
CONCLUSIONS
These findings address the basis of Wnt/β-catenin pathway activation in cervical cancer and provide combination immunotherapy options for targeting the FAT4/β-catenin/STT3/PD-L1 axis. Schematic cartoons showing the antitumor immunity mechanism of FAT4. (left) when Wnts bind to their receptors, which are made up of Frizzled proteins and LRP5/6, the cytoplasmic protein DVL is activated, inducing the aggregation of degradation complexes (AXIN, GSK3β, CK1, APC) to the receptor. Subsequently, stable β-catenin translocates into the nucleus and binds to TCF/LEF and TCF7L2 transcription factors, leading to target genes transcription. The catalytically active subunit of oligosaccharyltransferase, STT3A, enhances PD-L1 glycosylation, and N-glycosylated PD-L1 translocates to the cell membrane via the ER-to-Golgi pathway, resulting in immune evasion. (Right) FAT4 exerts antitumor immunity mainly through following mechanisms: (i) FAT4 binds to β-catenin and antagonizes its nuclear localization, promotes phosphorylation and degradation of β-catenin by the degradation complexes (AXIN1, APC, GSK3β, CK1); (ii) FAT4 inhibits PD-L1 and STT3A transcription in a β-catenin-dependent manner and induces aberrant PD-L1 glycosylation and ubiquitination-dependent degradation; (iii) Promotes activation of cytotoxic T lymphocytes (CTL) and infiltration into the tumor microenvironment.
Topics: Animals; Female; Humans; Mice; B7-H1 Antigen; beta Catenin; Cadherins; Glycogen Synthase Kinase 3 beta; Tumor Microenvironment; Tumor Suppressor Proteins; Uterine Cervical Neoplasms
PubMed: 37658376
DOI: 10.1186/s13046-023-02758-2 -
Cell May 2024Novel antibiotics are urgently needed to combat the antibiotic-resistance crisis. We present a machine-learning-based approach to predict antimicrobial peptides (AMPs)...
Novel antibiotics are urgently needed to combat the antibiotic-resistance crisis. We present a machine-learning-based approach to predict antimicrobial peptides (AMPs) within the global microbiome and leverage a vast dataset of 63,410 metagenomes and 87,920 prokaryotic genomes from environmental and host-associated habitats to create the AMPSphere, a comprehensive catalog comprising 863,498 non-redundant peptides, few of which match existing databases. AMPSphere provides insights into the evolutionary origins of peptides, including by duplication or gene truncation of longer sequences, and we observed that AMP production varies by habitat. To validate our predictions, we synthesized and tested 100 AMPs against clinically relevant drug-resistant pathogens and human gut commensals both in vitro and in vivo. A total of 79 peptides were active, with 63 targeting pathogens. These active AMPs exhibited antibacterial activity by disrupting bacterial membranes. In conclusion, our approach identified nearly one million prokaryotic AMP sequences, an open-access resource for antibiotic discovery.
PubMed: 38843834
DOI: 10.1016/j.cell.2024.05.013 -
Frontiers in Aging 2023Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a range of clinical symptoms, including poikiloderma, juvenile cataracts, short... (Review)
Review
Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a range of clinical symptoms, including poikiloderma, juvenile cataracts, short stature, sparse hair, eyebrows/eyelashes, nail dysplasia, and skeletal abnormalities. While classically associated with mutations in the gene, which encodes a DNA helicase involved in DNA replication and repair, three additional genes have been recently identified in RTS: , encoding a subunit of the APC/C complex; which encodes a nuclease/helicase involved in DNA repair; and , encoding a poorly characterized protein implicated in excitatory synapse formation and splicing. Here, we review the clinical spectrum of RTS patients, analyze the genetic basis of the disease, and discuss molecular functions of the affected genes, drawing some novel genotype-phenotype correlations and proposing avenues for future studies into this enigmatic disorder.
PubMed: 38021400
DOI: 10.3389/fragi.2023.1296409 -
Frontiers in Neuroscience 2023Epilepsy is one of the most common neurologic disorders that is characterized by recurrent seizures, and depending on the type of seizure, it could lead to a severe... (Review)
Review
Epilepsy is one of the most common neurologic disorders that is characterized by recurrent seizures, and depending on the type of seizure, it could lead to a severe outcome. Epilepsy's mechanism of development is not fully understood yet, but some of the common features of the disease are blood-brain barrier disruption, microglia activation, and neuroinflammation. Those are also targets of activated protein C (APC). In fact, by downregulating thrombin, known as a pro-inflammatory, APC acts as an anti-inflammatory. APC is also an anti-apoptotic protein, instance by blocking p53-mediated apoptosis. APC's neuroprotective effect could prevent blood-brain barrier dysfunction by acting on endothelial cells. Furthermore, through the downregulation of proapoptotic, and proinflammatory genes, APC's neuroprotection could reduce the effect or prevent epilepsy pathogenesis. APC's activity acts on blood-brain barrier disruption, inflammation, and apoptosis and causes neurogenesis, all hallmarks that could potentially treat or prevent epilepsy. Here we review both Activated Protein C and epilepsy mechanism, function, and the possible association between them.
PubMed: 37901428
DOI: 10.3389/fnins.2023.1251017 -
Genetics in Medicine : Official Journal... Feb 2024The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and...
Gene-specific ACMG/AMP classification criteria for germline APC variants: Recommendations from the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel.
PURPOSE
The Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (VCEP) was established by the International Society for Gastrointestinal Hereditary Tumours and the Clinical Genome Resource, who set out to develop recommendations for the interpretation of germline APC variants underlying Familial Adenomatous Polyposis, the most frequent hereditary polyposis syndrome.
METHODS
Through a rigorous process of database analysis, literature review, and expert elicitation, the APC VCEP derived gene-specific modifications to the ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) variant classification guidelines and validated such criteria through the pilot classification of 58 variants.
RESULTS
The APC-specific criteria represented gene- and disease-informed specifications, including a quantitative approach to allele frequency thresholds, a stepwise decision tool for truncating variants, and semiquantitative evaluations of experimental and clinical data. Using the APC-specific criteria, 47% (27/58) of pilot variants were reclassified including 14 previous variants of uncertain significance (VUS).
CONCLUSION
The APC-specific ACMG/AMP criteria preserved the classification of well-characterized variants on ClinVar while substantially reducing the number of VUS by 56% (14/25). Moving forward, the APC VCEP will continue to interpret prioritized lists of VUS, the results of which will represent the most authoritative variant classification for widespread clinical use.
Topics: Humans; Genetic Testing; Genetic Variation; Adenomatous Polyposis Coli; Germ-Line Mutation; Germ Cells
PubMed: 37800450
DOI: 10.1016/j.gim.2023.100992 -
Digestive Diseases and Sciences Jul 2023The most prevalent type of intestinal polyposis, colorectal adenomatous polyposis (CAP), is regarded as a precancerous lesion of colorectal cancer with obvious genetic... (Review)
Review
The most prevalent type of intestinal polyposis, colorectal adenomatous polyposis (CAP), is regarded as a precancerous lesion of colorectal cancer with obvious genetic characteristics. Early screening and intervention can significantly improve patients' survival and prognosis. The adenomatous polyposis coli (APC) mutation is believed to be the primary cause of CAP. There is, however, a subset of CAP with undetectable pathogenic mutations in APC, known as APC (-)/CAP. The genetic predisposition to APC (-)/CAP has largely been associated with germline mutations in some susceptible genes, including the human mutY homologue (MUTYH) gene and the Nth-like DNA glycosylase 1 (NTHL1) gene, and DNA mismatch repair (MMR) can cause autosomal recessive APC (-)/CAP. Furthermore, autosomal dominant APC (-)/CAP could occur as a result of DNA polymerase epsilon (POLE)/DNA polymerase delta 1 (POLD1), axis inhibition protein 2 (AXIN2), and dual oxidase 2 (DUOX2) mutations. The clinical phenotypes of these pathogenic mutations vary greatly depending on their genetic characteristics. Therefore, in this study, we present a comprehensive review of the association between autosomal recessive and dominant APC (-)/CAP genotypes and clinical phenotypes and conclude that APC (-)/CAP is a disease caused by multiple genes with different phenotypes and interaction exists in the pathogenic genes.
Topics: Humans; Adenomatous Polyposis Coli; Mutation; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Germ-Line Mutation; Phenotype; Genes, APC
PubMed: 36862359
DOI: 10.1007/s10620-023-07890-9 -
Clinics in Colon and Rectal Surgery Nov 2023Desmoid tumors (DT) represent the second high risk of tumor in familial adenomatous polyposis (FAP) patients. Although FAP-associated DTs (FAP-DT) are caused by germline... (Review)
Review
Desmoid tumors (DT) represent the second high risk of tumor in familial adenomatous polyposis (FAP) patients. Although FAP-associated DTs (FAP-DT) are caused by germline mutations in the adenomatous polyposis coli (APC) gene, extracolonic manifestations, sex, family history, genotype, and the ileal pouch anal anastomosis procedure are all linked to the development of DTs in FAP patients. Multidisciplinary management has replaced aggressive surgery as the preferred treatment of DTs. There is growing evidence to support the use of active surveillance strategy as first-line treatment for FAP-DT patients. Radiotherapy for intra-abdominal desmoids is now rarely used because of severe late toxicity. Pharmacotherapy, however, represents a promising future with the improvement of traditional cytotoxic drugs and the investigation of targeted drugs. Although nonsurgery treatment has been used widely nowadays, surgery remains the mainstay when symptomatic or life-threatening DTs are present. Further research will be needed for more optimal clinical practice.
PubMed: 37795470
DOI: 10.1055/s-0043-1767709 -
Seminars in Cell & Developmental Biology Dec 2023Mutations in the gene encoding the Adenomatous polyposis coli protein (APC) were discovered as driver mutations in colorectal cancers almost 30 years ago. Since then,... (Review)
Review
Mutations in the gene encoding the Adenomatous polyposis coli protein (APC) were discovered as driver mutations in colorectal cancers almost 30 years ago. Since then, the importance of APC in normal tissue homeostasis has been confirmed in a plethora of other (model) organisms spanning a large evolutionary space. APC is a multifunctional protein, with roles as a key scaffold protein in complexes involved in diverse signalling pathways, most prominently the Wnt signalling pathway. APC is also a cytoskeletal regulator with direct and indirect links to and impacts on all three major cytoskeletal networks. Correspondingly, a wide range of APC binding partners have been identified. Mutations in APC are extremely strongly associated with colorectal cancers, particularly those that result in the production of truncated proteins and the loss of significant regions from the remaining protein. Understanding the complement of its role in health and disease requires knowing the relationship between and regulation of its diverse functions and interactions. This in turn requires understanding its structural and biochemical features. Here we set out to provide a brief overview of the roles and function of APC and then explore its conservation and structure using the extensive sequence data, which is now available, and spans a broad range of taxonomy. This revealed conservation of APC across taxonomy and new relationships between different APC protein families.
Topics: Humans; Adenomatous Polyposis Coli Protein; Adenomatous Polyposis Coli; Mutation; Cytoskeleton; Wnt Signaling Pathway
PubMed: 37095033
DOI: 10.1016/j.semcdb.2023.04.004