Duncan NRI Faculty and Staff Publications
Publication Date
5-8-2023
Journal
EMBO Molecular Medicine
DOI
10.15252/emmm.202216877
PMID
36987696
PMCID
PMC10165358
PubMedCentral® Posted Date
3-29-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Mice, Animals, Kidney, Kidney Neoplasms, Birt-Hogg-Dube Syndrome, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Transcription Factors, Carcinogenesis, Cysts, BHD, cysts, kidney cancer, TFE3, TFEB
Abstract
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.
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Genetic Phenomena Commons, Medical Genetics Commons, Nephrology Commons, Neurology Commons, Neurosciences Commons