Characterizing the tumor suppressor activity of FLCN in Birt-Hogg-Dube syndrome through transcriptiomic and proteomic analysis
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ABSTRACT:
PROVIDER: PRJNA1191458 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31534841_1.fastq.gz | Fastqsanger.gz | |||
| SRR31534841_2.fastq.gz | Fastqsanger.gz | |||
| SRR31534842_1.fastq.gz | Fastqsanger.gz | |||
| SRR31534842_2.fastq.gz | Fastqsanger.gz | |||
| SRR31534843_1.fastq.gz | Fastqsanger.gz |
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Project description:Birt-Hogg-Dube (BHD) syndrome patients are uniquely susceptible to all renal tumour subtypes. The underlying mechanism of carcinogenesis is unclear. To study cancer development in BHD, we used human proximal kidney (HK2) cells with short-term and long-term folliculin (FLCN) knockdown. HK2 cells lacking FLCN had an altered transcriptome profile with cell cycle control gene enrichment. G1/S cell cycle checkpoint signaling was compromised with heightened protein levels of cyclin D1 (CCND1) and hyperphosphorylation of retinoblastoma 1 (RB1). Taken together with our proteomic work, our findings indicate that long-term FLCN loss and associated cell cycle defects in BHD patients could contribute to their increased risk of cancer.
2024-11-28 | GSE283021 | GEO
Project description:Growing tumors exist in metabolically compromised environments that require activation of multiple pathways to scavenge nutrients to support accelerated rates of growth. The FLCN tumor suppressor complex (FLCN, FNIP1, FNIP2) has been implicated in the regulation of energy homeostasis via two metabolic master kinases: AMPK and mTORC1. Loss-of-function mutations of the FLCN tumor suppressor complex have only been reported in renal tumors in patients with the rare Birt-Hogg-Dube syndrome. Here we reveal that FLCN, FNIP1, and FNIP2 are downregulated in many human cancers including poor prognosis invasive basal-like breast carcinomas where AMPK and TFE3 targets are activated compared to the luminal, less aggressive subtypes. We show that FLCN loss in luminal subtypes promotes tumor growth through TFE3 activation and subsequent induction of several pathways including autophagy, lysosomal biogenesis, aerobic glycolysis, and angiogenesis. Strikingly, induction of aerobic glycolysis and angiogenesis in FLCN deficient cells was dictated by the activation of PGC-1⍺/HIF-1⍺ pathway, which we show to be TFE3-dependent, directly linking TFE3 to Warburg metabolic reprogramming and angiogenesis. Thus, FLCN loss induces TFE3-dependent breast tumor growth through activation of multiple mechanisms, including previously unreported roles in aerobic glycolysis and angiogenesis. These findings could point to a general role of a deregulated FLCN/TFE3 tumor suppressor pathway in human cancers.
2020-12-23 | GSE163791 | GEO
Project description:In Birt-Hogg-Dubé (BHD) syndrome, germline mutations in the Folliculin (FLCN) gene lead to an increased risk of renal cancer. To address if FLCN is involved regulating cellular signaling pathways via protein and receptor phosphorylation we determined comprehensive complete phosphoproteomic profiles of FLCNPOS and FLCNNEG human renal tubular epithelial cells (RPTEC/TERT1). In total, 15744 phosphorylated peptides were identified, residing on 4329 phosphorylated proteins. Kinase activity inference analysis revealed that FLCN loss elevates phosphorylation of numerous kinases, including tyrosine kinases EPHA2 and MET, as well as activation of downstream MAPK1/3/6 and 8. Three non-canonical phosphorylation sites on EGFR (Tyr1125, Tyr1138 and Tyr1172) were higher phosphorylated upon FLCN loss together with enhanced phosphorylated EGFR substrates ABI, EPS8, ERRFL1, STAT1, PTK2 and CTNND1. In concordance, phosphosite specific signature analyses revealed an enrichment for EGFR signaling in FLCNNEG cells. Interestingly, we detected FLCN dependent phosphorylation of PIK3CD but no canonical downstream Akt/mTOR activation. In agreement with the induction of the E-box transcriptional gene expression signature upon FLCN loss, here we identified that phosphorylation of TFEB on Ser109, Ser114 and Ser122 is dependent on FLCN and absence of this phosphorylation results in constitutive nuclear localization of this transcription factor in FLCNNEG cells. Together, our study reveals enhanced phosphorylation of specific kinases and substrates in FLCNNEG renal epithelial cells, providing important insights in BHD-associated renal tumorigenesis and offering novel handles for the design of targeted therapies.
2022-07-11 | PXD025798 | Pride
Project description:The “Warburg effect” describes the use of aerobic glycolysis by cancer cells to fuel their growth. Lactate dehydrogenase-A (LDHA) is key to this process and catalyzes the interconversion of pyruvate and lactate. Here we used a proteomic approach to identify LDHA as a binding partner of the tumor suppressor FLCN. Canonically, LDHA is thought to be a substrate-regulated enzyme, however our data show that FLCN uncompetitively inhibits LDHA activity by restricting movement of its active site loop. This inhibition appears to be critical in normal cells, as we show FLCN binds to and tightly regulates LDHA activity in order to preserve metabolic homeostasis. Pathogenic mutations of FLCN are associated with LDHA hyperactivity and kidney tumor formation, suggesting a mechanism for FLCN tumor suppressive function. We have identified a cell-permeant ten amino acid peptide based on the FLCN sequence that enters these tumors and inhibits LDHA ex vivo. In a broader context, renal cell carcinomas experience the Warburg effect and show FLCN dissociation from LDHA. Cells that experience this metabolic shift depend on the hyperactivity of LDHA, as previous work has shown attenuation or inhibition of LDHA leads to programmed cell death. Treating these cells with the FLCN-derived peptide causes apoptosis, strongly suggesting that the glycolytic shift of cancer cells is the result of FLCN inactivation or disassociation from LDHA. Taken together, FLCN-mediated inhibition of LDHA provides a new paradigm for the regulation of glycolysis.
2021-08-05 | PXD018410 | Pride
Project description:Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disorder that is characterized by the clinical triad of benign skin tumors - so-called fibrofolliculomas, recurrent pneumothoraces due to pulmonary cysts and the formation of kidney tumors. The molecular function of Folliculin (FLCN), the protein product of the BHD gene mutated in this syndrome, has remained elusive to a large extent. Animal models such as mouse, rat and canine models have been used to elucidate parts of the pathway in which FLCN plays a role showing it to interfere with AMP-kinase and mTOR signaling. Caenorhabditis elegans provides - due to its simple genetic amenability and large brood size - the perfect tool to study signal transduction pathways in detail. Thus, we decided to examine F22D3.2 (flcn-1) - a putative orthologue of FLCN in the nematode. We established the first gene expression profiles of a strain harboring a mutation in flcn-1 compared to WTN2 allowing for a first insight into the function of this gene in C. elegans. This study examines the transcriptome of the flcn-1 mutant strain RB1035 in comparison to WTN2 in order to identify differentially regulated genes. RNA was prepared from pre-reproductive adults in both WTN2 and RB1035 (harboring a flcn-1 mutant allele, mutant worms had been backcrossed wo WTN2 8 times) using biological triplicates. RNA was labeled and hybridized to Agilent C. elegans whole genome microarrays and scanned using a Agilent Technologies Scanner G2505C US22502540.
2012-12-31 | E-GEOD-43207 | biostudies-arrayexpress
Project description:Birt-Hogg-Dubé syndrome is an autosomal dominantly inherited disorder that is characterized by the clinical triad of benign skin tumors - so-called fibrofolliculomas, recurrent pneumothoraces due to pulmonary cysts and the formation of kidney tumors. The molecular function of Folliculin (FLCN), the protein product of the BHD gene mutated in this syndrome, has remained elusive to a large extent. Animal models such as mouse, rat and canine models have been used to elucidate parts of the pathway in which FLCN plays a role showing it to interfere with AMP-kinase and mTOR signaling. Caenorhabditis elegans provides - due to its simple genetic amenability and large brood size - the perfect tool to study signal transduction pathways in detail. Thus, we decided to examine F22D3.2 (flcn-1) - a putative orthologue of FLCN in the nematode. We established the first gene expression profiles of a strain harboring a mutation in flcn-1 compared to WTN2 allowing for a first insight into the function of this gene in C. elegans. This study examines the transcriptome of the flcn-1 mutant strain RB1035 in comparison to WTN2 in order to identify differentially regulated genes.
2012-12-31 | GSE43207 | GEO
Project description:Loss of functional FLCN mutations are known to be the cause of Birt-Hogg-Dubé (BHD) syndrome, in which pulmonary cysts are presented in up to 90% of the patients. Lack of the related disease models in vivo poses a significant barrier to understanding the pathogenic mechanisms, including how the cysts develop and what molecular signaling pathways are involved. In this study, we selectively deleted Flcn specifically in lung mesenchymal cells using a Tbx4-rtTA/TetO-Cre driver. These mice exhibit defective postnatal lung alveolarization. Most strikingly, alveolar enlargement continues into adulthood in these mice, accompanied by bilateral pulmonary cyst formation that resemble human BHD. Interestingly, Flcn deletion in lung epithelial cells alone did not exhibit any alveolar enlargement. No synergistic or additive effects were detected in mouse lungs with combined Flcn deletion in both epithelial and mesenchymal compartments compared to the mice with lung mesenchymal Flcn knockout. We have compared differential gene expression of lung tissues between Flcn knockout in mesenchyme and wild type control mice by RNA-seq.
2025-12-02 | GSE266599 | GEO
Project description:Germline inactivating mutations in Folliculin (FLCN) cause Birt–Hogg–Dubé (BHD) syndrome, a rare autosomal dominant disorder predisposing to kidney tumors. FLCN is a conserved, essential gene that has been linked to diverse cellular processes but the mechanisms by which FLCN prevents kidney cancer remain unknown Here we show that FLCN loss activates E-box target genes in human renal tubular epithelial cells (RPTEC/TERT1), including RRAGD, yet without modifying mTORC1 activity. Surprisingly, inactivation of FLCN or its binding partners FNIP1/FNIP2 activates interferon response genes but independently of interferon. Mechanistically, FLCN loss promotes recruitment of STAT2 to chromatin and slows cellular proliferation. Our integrated analysis identifies STAT1/2 as a novel target of FLCN in renal cells and BHD tumors. STAT1/2 activation appears to counterbalance TFE3-directed hyper-proliferation and may influence the immune response. These findings shed light on unique roles of FLCN in human renal tumorigenesis and pinpoint novel prognostic biomarkers.
2021-02-11 | PXD021346 | Pride
Project description:differential display between WT and FLCN KO
2016-11-11 | GSE89762 | GEO
Project description:Renal cancer accounts for 2% to 3% of all adult malignancies in the US. In 2011 more than 64,770 new cases and 13,000 deaths were reported and the incidence is steadily increasing by 2.5% per year. Clear cell renal carcinoma (ccRCC) represents the majority (85% to 90%) of adult kidney cancers and is the most malignant. This cancer is characterized by an early loss of the von Hippel-Lindau tumor suppressor (VHL) on short arm of chromosome 3 in the majority of tumors (80%). It is a classic knowledge that loss of VHL results in an increased accumulation and activity of the hypoxia-inducible transcription factor (HIF), which in turns activates expression of genes promoting tumor growth. In that respect, induction of angiogenic factors induces blood flow through the tumors and delivery of nutrients and oxygen to cancer cells, while induction of genes inducing anaerobic glycolysis supports adaptation to reduced nutrients availability and shifts towards metabolic pathways promoting tumor growth. Recently we have discovered another tumor suppressing pathway regulated by VHL. We found that VHL is a major regulator of the process of macroautophagy (autophagy) (ref). We identified that VHL induces expression of a microRNA, miR-204, which in turn inhibits activity of a major regulator required for the formation of autophagosome, LC3B. LC3B-mediated autophagy is necessary for the ccRCC tumor growth, and inhibition of this process by VHL and miR-204 significantly contributes to the tumor suppression. Most importantly, we discovered that VHL by inhibiting activity of HIF, induced expression and activity of an LC3B paralog, LC3C. In contrast to LC3B, LC3C acts as a tumor suppressor, indicating the specificity and complexity of different autophagic programs. Integrating these novel data with the established role of VHL in regulating angiogenesis produces a more global picture of VHL as a master tumor suppressor that regulates nutrient access for renal cancer cells from both extracellular and intracellular sources. In the process of searching for other genes induced by VHL that could participate in the tumor suppressing activity of VHL, we discovered that reconstitution of VHL in RCC cells induces enrichment of genes expressed from the Smith-Magenis locus (SM), located on the short arm of chromosome 17p11.2. Smith-Magenis syndrome is a complex neurobehevioural disorder, characterized by intellectual impairment, craniofacial and skeletal anomalies and sleep disturbance. Recently, deletions or mutations of one specific gene in the SM locus, RAI1, (retinoic acid induced 1), were shown to be responsible for the syndrome. Interestingly, this locus contains another kidney tumor suppressor gene, folliculin (FLCN), of which activity is lost in the genetic dominant disorder, Birt-Hogg-Dube syndrome (BHD). BHD is characterized by skin fibrofolliculomas, pulmonary cysts and spontaneous pneumothorax, as well as renal cancer of mixed histological types, including chromophobe, oncocytic, clear cell and papillary type. Here we show that VHL regulates expression of FLCN, and in turn FLCN contributes to the VHL-mediated suppression of tumor growth. Two-condition experiment, VHL(-) vs. VHL(+). 4 biological replicates in each group. Two dual-channel arrays with VHL(+) on Cy5 and VHL(-) on Cy3, and two dual-channel arrays with flipped samples.
2013-05-20 | E-GEOD-47106 | biostudies-arrayexpress