EGR1 Drives Cell Proliferation by Directly Stimulating TFEB Transcription in Response to Starvation

Authors

Marcella Cesana
Gennaro Tufano
Francesco Panariello
Nicolina Zampelli
Susanna Ambrosio
Rossella De Cegli
Margherita Mutarelli
Lorenzo Vaccaro
Micheal J Ziller
Davide Cacchiarelli
Diego L Medina
Andrea Ballabio

Publication Date

3-1-2023

Journal

PLoS Biology

DOI

10.1371/journal.pbio.3002034

PMID

36888606

PMCID

PMC9994711

PubMedCentral® Posted Date

3-8-2023

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Humans, Mechanistic Target of Rapamycin Complex 1, Autophagy, Lysosomes, Cell Proliferation, Early Growth Response Protein 1, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors

Abstract

The stress-responsive transcription factor EB (TFEB) is a master controller of lysosomal biogenesis and autophagy and plays a major role in several cancer-associated diseases. TFEB is regulated at the posttranslational level by the nutrient-sensitive kinase complex mTORC1. However, little is known about the regulation of TFEB transcription. Here, through integrative genomic approaches, we identify the immediate-early gene EGR1 as a positive transcriptional regulator of TFEB expression in human cells and demonstrate that, in the absence of EGR1, TFEB-mediated transcriptional response to starvation is impaired. Remarkably, both genetic and pharmacological inhibition of EGR1, using the MEK1/2 inhibitor Trametinib, significantly reduced the proliferation of 2D and 3D cultures of cells displaying constitutive activation of TFEB, including those from a patient with Birt-Hogg-Dubé (BHD) syndrome, a TFEB-driven inherited cancer condition. Overall, we uncover an additional layer of TFEB regulation consisting in modulating its transcription via EGR1 and propose that interfering with the EGR1-TFEB axis may represent a therapeutic strategy to counteract constitutive TFEB activation in cancer-associated conditions.