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Gene expression data from FLCN-restored UOK257-2 renal cancer cells

ABSTRACT: UOK257 cell line was derived from a BHD patient. It harbors a germline mutation in FLCN (c.1285dupC) and LOH. UOK257-2 cells were generated from UOK257 cells by introducing wildtype FLCN using retrovirus. FLCN inactivation induces TFE3 transcriptional activity by increasing its nuclear localization. Thus expression microarray was used to identify the genes regulated by FLCN and TFE3.

ORGANISM(S): Homo sapiens

PROVIDER: GSE23614 | GEO | 2010/10/11

SECONDARY ACCESSION(S): PRJNA129945

REPOSITORIES: GEO

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Gene expression data from FLCN-restored UOK257-2 renal cancer cells

Project description:UOK257 cell line was derived from a BHD patient. It harbors a germline mutation in FLCN (c.1285dupC) and LOH. UOK257-2 cells were generated from UOK257 cells by introducing wildtype FLCN using retrovirus. FLCN inactivation induces TFE3 transcriptional activity by increasing its nuclear localization. Thus expression microarray was used to identify the genes regulated by FLCN and TFE3. UOK257-2 cells expressing wildtype FLCN were transfected with 1) scrambled, 2) FLCN, 3) TFE3 and 4)FLCN/TFE3 siRNAs with Lipofectamine 2000 transfection reagent. Cells were harvested 3 days after transfection and RNAs were isolated using Trizol reagent and RNeasy Mini Kit. The genes induced by FLCN siRNA and reduced by TFE3 siRNA were chosen as a candidate genes regulated by FLCN and TFE3.

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Loss of FLCN-FNIP1/2 Induces a Non-Canonical Interferon 1 Response in Human Renal Tubular Epithelial Cells

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

TFEB AND TFE3 DRIVE KIDNEY CYSTOGENESIS AND TUMORIGENESIS

Project description:Birt-Hogg-Dubè (BHD) syndrome is an inherited condition caused by loss-of-function mutations in the gene encoding the tumor-suppressor protein folliculin (FLCN) and frequently associated with kidney cysts and cancer. FLCN acts as a negative regulator of TFEB and TFE3 transcription factors, master controllers of lysosomal biogenesis and autophagy, by enabling their phosphorylation by the mechanistic Target Of Rapamycin Complex 1 (mTORC1). We previously showed that deletion of TFEB rescued the renal cystic phenotype of kidney-specific Flcn KO mice. Using Flcn/TFEB/TFE3 double and triple KO mice we now show that both TFEB and TFE3 contribute, in a differential and cooperative manner, to kidney cystogenesis. Importantly, silencing of either TFEB or TFE3 rescued tumorigenesis in patient-derived xenografts (PDXs) generated from a kidney tumor of a BHD patient. Furthermore, transcriptome analyses performed in transgenic mice, PDXs and patient tumor samples revealed TFEB/TFE3 downstream targets that may contribute to their tumorigenic activity. Our findings demonstrate in disease-relevant models that TFEB and TFE3 are key drivers of kidney tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors.

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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.

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Phosphoproteomic analysis of the Folliculin (FLCN) tumor suppressor reveals FLCN-dependent kinase signaling and TFEB regulation

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.

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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

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