GSE209898
HeLa-FLCN KO upon Trametinib treatment [Trametinib_RNAseq]
Transcriptional regulation of gene expression plays a fundamental role in coordinating molecular and metabolic responses to stress conditions. The stress-responsive Transcription Factor EB (TFEB), the master controller of lysosomal biogenesis and autophagy, is regulated at the post-translational level by the nutrient-sensitive kinase complex TORC1. However, little is known about the transcriptional regulation of TFEB in physiological and pathological conditions. Here, we show that during starvation, the immediate-early gene EGR1 binds to the TFEB promoter and positively regulates TFEB expression. EGR1 depletion dampened TFEB-mediated transcriptional response to starvation and significantly inhibited cell proliferation in cellular and 3D spheroid models of Birt-Hogg-Dube' (BHD) syndrome, a TFEB-driven inherited cancer condition. Consistently, the MEK1/2 inhibitor Trametinib, known to inhibit EGR1 expression, suppressed the proliferation of BHD patient-derived cancer cells, suggesting that pharmacological inhibition of the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions. Overall design: RNA-seq of HeLa FLCN KO cells treated with Trametinb