TFEB and TFE3 drive kidney cystogenesis and tumorigenesis

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. image TFEB and TFE3 transcription factors are master regulators of cell metabolism. This study shows that in Birt‐Hogg‐Dubé (BHD) hereditary cancer syndrome, these factors concomitantly activate cellular catabolic and anabolic pathways, playing a key role in kidney cystogenesis and tumorigenesis. Genetic interaction studies revealed that TFEB and TFE3 have a differential and cooperative role in the kidney phenotype of a mouse model of BHD syndrome. Transcriptomic and proteomic analyses of tumor samples from BHD patients showed upregulation of the TFEB/TFE3 transcriptional program and induction of both lysosomal and mTORC1 pathways. Depletion of TFEB or TFE3 fully abrogated the growth of BHD renal tumor cells in xenograft experiments, indicating that both genes are key drivers of tumorigenesis.