Elucidating the role of glycogen debranching enzyme AGL in bladder carcinogenesis by generation and characterization of knockout mice
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ABSTRACT:
PROVIDER: PRJNA450320 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7007620_1.fastq.gz | Fastqsanger.gz | |||
| SRR7007620_2.fastq.gz | Fastqsanger.gz | |||
| SRR7007621_1.fastq.gz | Fastqsanger.gz | |||
| SRR7007621_2.fastq.gz | Fastqsanger.gz | |||
| SRR7007614_1.fastq.gz | Fastqsanger.gz |
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Project description:Amylo-alpha-1-6-glucosidase-4-alpha-glucanotransferase (AGL) is an enzyme primarily responsible for glycogen debranching. Inactivating germline mutations lead to glycogen storage disease III (GSDIII). AGL was found to be a tumor suppressor in xenograft models of bladder cancer (BC) and low levels of expression in BC were associated with poor patient prognosis. However, the impact of AGL levels in normal tissues on susceptibility to carcinogenesis is unknown. We address this gap by developing a full body/germline AGL knock-out (AGL-FBKO) that recapitulates biochemical and histological features of GSDIII. AGL-FBKO mice exposed to N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) had higher BC incidence at several time points following exposure, compared to wild type littermates (AGL-FBWT). To determine if this increased BC prevalence was due to decreased expression of AGL in the urothelium, we derived a urothelium specific conditional AGL knock-out (AGL-cKO) mouse driven by a Uroplakin II-Cre/loxP system. BBN experiments with these mice revealed AGL-cKO had higher BC incidence than mice without AGL knock-out (AGL-cWT). RNA-sequencing revealed that tumors from AGL-FBKO had 19 differentially expressed genes compared to AGL-FBWT mice. An “AGL Loss” gene signature was developed and found to successfully stratify normal and tumor samples in two BC patient datasets. These results support the role of AGL as a tumor suppressor. Our work suggests that evaluating AGL expression levels, or AGL KO gene signature scores, in normal urothelium may serve as a predictor for increased risk of BC development in individuals with carcinogenic exposures, such as smoking.
2020-03-31 | GSE113158 | GEO
Project description:DNA methylation profile in rat bladder carcinogenesis treated with dimethylarsinic acid.
2023-11-06 | GSE243372 | GEO
Project description:Glycogen is the largest soluble cytosolic macromolecule and considered as the principal storage form of glucose. Cancer cells generally increase their glucose consumption and rewire their metabolism towards aerobic glycolysis to promote growth. Here we report that glycogen accumulation is a key initiating oncogenic event and essential for malignant transformation. RNA-sequencing analysis reveals that G6PC, an enzyme catalyzing the last step of glycogenolysis, is frequently downregulated to augment glucose storage in pro-tumor cells. Accumulated glycogen undergoes liquid-liquid phase separation undergoes liquid-liquid phase separation, which results in the assembly of the laforin-Mst1/2 complex and consequently traps Hippo kinases Mst1/2 in glycogen liquid droplets to relieve their inhibition on Yap. Moreover, G6PC or another glycogenolysis enzyme PYGL deficiency in both human and mice result in glycogen storage disease with enlarged liver size and cancer development, phenocopying Hippo deficiency. Consistently, elimination of glycogen accumulation abrogates liver enlargement and cancer incidence, whereas increasing glycogen storage accelerates tumorigenesis. Thus, we concluded that glycogen not only provides nutrition and energy to the cells but also functions as a key initiating oncogenic metabolite, which physically blocks Hippo signaling through glycogen phase separation to augment pro-tumor cell initiation and progression.
2021-10-06 | GSE148933 | GEO
Project description:In vitro and in vivo studies including single cell sequencing showed that LPAR6 and CAB39L play a major role in regulating basal to luminal urothelial differentiation. Their loss of function contributed to bladder carcinogenesis by dysregulating urothelial differentiation program and sensitizing the urothelium to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) induced cancers, which recapitulated luminal and basal subtypes of human bladder cancer.
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Project description:Grainyhead-like transcription factor 3 (GRHL3) is known to affect cancer development depending on subtypes in various entities. Here, we analyzed the subtype-specific role of GRHL3 in bladder carcinogenesis comparing common urothelial carcinoma (UC) with squamous bladder cancers (sq-BLCA). We examined GRHL3 mRNA and protein expression in cohorts of patient samples, its prognostic role as well as its functional impact on tumorigeneses in different molecular and histopathological subtypes of bladder cancer. We showed for GRHL3 a reverse expression in squamous and urothelial bladder cancer subtypes. Stably GRHL3 overexpressing EJ28 and SCaBER in vitro models revealed a tumor suppressive function in squamous and a oncogenic role in the urothelial cancer cells affecting cell migratory and invasive capacities. Transcriptomic profiling demonstrated highly subtype specific GRHL3 regulated expression networks coined by enrichment of genes involved in integrin mediated pathways. In SCaBER loss of RhoA GTPase activity was demonstrated associated with co-regulation of EIF4E3, a potential tumor suppressor gene. Thus, our data provide for the first time a detailed insight into the role of the transcription factor GRHL3 in different histopathological subtypes of bladder cancer.
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Project description:In this study, we aimed at uncovering the molecular mechanisms underlying POMC neuron sensory activation and the mediated behavioral and metabolic processes. Unexpectedly, we found that glycogen metabolism is rapidly engaged in POMC neurons upon sensory food perception. Genetic deletion of glycogen synthase, the sole enzyme able to make glycogen in vivo, in POMC neurons impedes food-related sensory activation while causing impairments in food awareness, short-term food intake and insulin release. These perturbations associate with whole-body metabolic defects, including overweight and insulin resistance, that are exacerbated by high-dense diets or ageing. Collectively, our study identifies glycogen metabolism as an unanticipated mechanistic driver of POMC neuron sensory activation and provides paradigm-shift evidences of the importance of neuronal glycogen for physiology.
2024-01-31 | GSE224274 | GEO
Project description:Aberrant DNA Methylation in Dimethylarsinic Acid-induced Rat Bladder Carcinogenesis
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Project description:Acid alpha-glucosidase (GAA) is a lysosomal glycogen-catabolizing enzyme, a deficiency in which leads to Pompe disease. Pompe disease can be treated with systemic recombinant human GAA (rhGAA) enzyme replacement therapy (ERT), but the current standard of care has poor uptake in skeletal muscles, limiting clinical efficacy. Further, it is unclear how the specific cellular processing steps of GAA post-delivery to lysosomes impact efficacy. GAA undergoes both proteolytic cleavage and glycan trimming within the endolysosomal pathway, yielding a more active enzyme for hydrolyzing its natural substrate glycogen. The relative contributions for each of these processing steps for increasing rhGAA glycogen hydrolytic activity are unclear. Here, we developed a tool kit of modified rhGAAs that allowed us to dissect the individual contributions of glycan trimming and proteolysis on maturation-associated increases in hydrolytic activity on glycogen. Chemical modifications of terminal sialic acids on N-glycans blocked sialidase activity in vitro and in cellulo, thereby preventing downstream glycan trimming without affecting proteolysis. This sialidase-resistant rhGAA displayed only partial activation following endolysosomal processing, as evidenced by lower catalytic efficiency on glycogen. We also generated enzymatically deglycosylated rhGAA that was shown to be partially activated despite not undergoing proteolytic processing. Taken together, these data suggest that an optimal rhGAA ERT would require both N-glycan and proteolytic processing to attain the most efficient enzyme kinetics for glycogen hydrolysis.
2021-05-05 | PXD025285 | Pride
Project description:Bladder carcinogenesis and tumour progression is accompanied by profound alterations in protein glycosylation. These include the presence of short chain O-glycans such as Tn and T antigens and their sialylated counterparts sialyl-Tn(STn) and sialyl-T(ST). The presence of such structures is commonly associated with poor prognosis. In search for prognosis biomarkers and novel therapeutic targets we have screened, using immunohistochemistry, a series of bladder tumours with differing clinicopathology for these short-chain O-glycans. Aiming at identifying protein targets, we have studied the O-glycoproteome of a pool of STn positive tumours from muscle invasive bladder cancer (MIBC) patients.
2017-08-17 | PXD006813 | Pride
Project description:Glycogen and lipid are major storage forms of energy that are tightly regulated by hormones and metabolic signals. Here, we evaluate the role of the glycogenic scaffolding protein PTG/R5 in energy homeostasis. We demonstrate that feeding mice a high-fat diet (HFD) increases hepatic glycogen, corresponding to increased PTG levels, increased activity of the mechanistic target of rapamycin complex 1 (mTORC1) and induced expression of sterol regulatory element binding protein 1c (SREBP1c). PTG promoter activity was increased by activation of mTORC1 and SREBP1, and PTG and glycogen levels were augmented in mice and cells in which mTORC1 is constitutively active. HFD-dependent increases in hepatic glycogen were prevented by deletion of the PTG gene in mice. Interestingly, PTG knockout mice fed HFD exhibited improved liver steatosis and decreased lipid levels in muscle, in coordination with decreased glycogen, suggesting possible crosstalk between glycogen and lipid stores in the overall control of energy metabolism. Together, these data suggest that transcriptional regulation of PTG by dietary and nutritional cues has profound effects on energy storage and metabolism.fi RNA-Seq analysis was used to characterize hepatic diet-associated gene expression changes between wild-type and PTG KO mice. Mice were maintained on a normal chow diet or a high-fat diet as indicated. 2-3 biological replicates per genotype/diet.
2014-06-13 | E-GEOD-45319 | biostudies-arrayexpress