| First Author | Di Malta C | Year | 2023 |
| Journal | EMBO Mol Med | Volume | 15 |
| Issue | 5 | Pages | e16877 |
| PubMed ID | 36987696 | Mgi Jnum | J:335554 |
| Mgi Id | MGI:7481394 | Doi | 10.15252/emmm.202216877 |
| Citation | Di Malta C, et al. (2023) TFEB and TFE3 drive kidney cystogenesis and tumorigenesis. EMBO Mol Med 15(5):e16877 |
| abstractText | Birt-Hogg-Dube (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. |
