| Title: |
TFEB and TFE3 drive kidney cystogenesis and tumorigenesis |
| Authors: |
Di Malta C; Zampelli A; Granieri L; Vilardo C; De Cegli R; Cinque L; Nusco E; Pece S; Tosoni D; Sanguedolce F; Sorrentino NC; Merino MJ; Nielsen D; Srinivasan R; Ball MW; Ricketts CJ; Vocke CD; Lang M; Karim B; Lanfrancone L; Schmidt LS; Linehan WM; Ballabio A |
| Contributors: |
C. Di Malta; A. Zampelli; L. Granieri; C. Vilardo; R. De Cegli; L. Cinque; E. Nusco; S. Pece; D. Tosoni; F. Sanguedolce; N. Sorrentino; M. Merino; D. Nielsen; R. Srinivasan; M. Ball; C. Rickett; C. Vocke; M. Lang; B. Karim; L. Lanfrancone; L. Schmidt; W. Linehan; A. Ballabio |
| Publication Year: |
2023 |
| Collection: |
The University of Milan: Archivio Istituzionale della Ricerca (AIR) |
| Subject Terms: |
BHD; cyst; kidney cancer; TFE3; TFEB; Settore BIOS-10/A - Biologia cellulare e applicata; Settore MEDS-02/A - Patologia generale |
| Description: |
Birt-Hogg-Dubé (BHD) syndrome is an inherited familial cancer syndrome characterized by the development of cutaneous lesions, pulmonary cysts, renal tumors and cysts and caused by loss-of-function pathogenic variants in the gene encoding the tumor-suppressor protein folliculin (FLCN). 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 have previously shown 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. Remarkably, the analysis of BHD patient-derived tumor samples revealed increased activation of TFEB/TFE3-mediated transcriptional program and silencing either of the two genes rescued tumorigenesis in human BHD renal tumor cell line-derived xenografts (CDXs). Our findings demonstrate in disease-relevant models that both TFEB and TFE3 are key drivers of renal tumorigenesis and suggest novel therapeutic strategies based on the inhibition of these transcription factors. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
info:eu-repo/semantics/altIdentifier/pmid/36987696; info:eu-repo/semantics/altIdentifier/wos/WOS:000958635200001; volume:15; issue:5; firstpage:1; lastpage:12; numberofpages:12; journal:EMBO MOLECULAR MEDICINE; https://hdl.handle.net/2434/1124317 |
| DOI: |
10.15252/emmm.202216877 |
| Availability: |
https://hdl.handle.net/2434/1124317; https://doi.org/10.15252/emmm.202216877 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.B0CD560E |
| Database: |
BASE |