MYC competes with MiT/TFE in regulating lysosomal biogenesis and autophagy through an epigenetic rheostat

Abstract

Coordinated regulation of the lysosomal and autophagic systems ensures basal catabolism and normal cell physiology, and failure of either system causes disease. Here we describe an epigenetic rheostat orchestrated by c-MYC and histone deacetylases that inhibits lysosomal and autophagic biogenesis by concomitantly repressing the expression of the transcription factors MiT/TFE and FOXH1, and that of lysosomal and autophagy genes. Inhibition of histone deacetylases abates c-MYC binding to the promoters of lysosomal and autophagy genes, granting promoter occupancy to the MiT/TFE members, TFEB and TFE3, and/or the autophagy regulator FOXH1. In pluripotent stem cells and cancer, suppression of lysosomal and autophagic function is directly downstream of c-MYC overexpression and may represent a hallmark of malignant transformation. We propose that, by determining the fate of these catabolic systems, this hierarchical switch regulates the adaptive response of cells to pathological and physiological cues that could be exploited therapeutically.

Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I

“…In search of an alternative method to boost NEU1 activity, we opted for romidepsin, a highly potent, brain-permeable HDAC class I-specific inhibitor [20,22]. This choice was based on the striking increase of normal NEU1 expression levels upon treatment of cells with HDAC inhibitors [14]. The response to romidepsin treatment was remarkably effective in all 12 sialidosis fibroblasts.…”

“…Given the growing number of patients with type I sialidosis, and the urgent need for treatments, it is crucial to look outside the box and experiment not only with conventional therapies but also with alternative ways to halt or ameliorate disease symptomatology. In line with this notion is the recent finding that the histone deacetylase (HDAC) inhibitor SAHA enhances NEU1 mRNA expression and NEU1 residual activity in fibroblasts from patients with both type I and type II sialidosis [14]. It is likely that other genetic/epigenetic modifiers as well as environmental factors, including specific diet regimens, and food supplements, could influence the levels of residual enzyme activity and the penetrance of specific phenotypes.…”

“…We have recently demonstrated that NEU1 mRNA expression responds to histone deacetylase (HDAC) inhibitors and that NEU1 levels are regulated by HDAC2, one of the 11 members of the HDAC family belonging to the classical class I HDAC [14]. Based on these findings, we wanted to test the effect of another Food and Drug Administration (FDA)-approved HDAC inhibitor, romidepsin, that targets more specifically class I HDAC [20][21][22], on all 12 type I sialidosis fibroblasts included in this study.…”

Transcription factor competition regulates lysosomal biogenesis and autophagy

“…In our publication, we addressed in part this question by demonstrating that MiT/TFE are regulated by an epigenetic and transcriptional network, another serendipitous finding. 7 We wanted to understand how the gene encoding for the lysosomal sialidase, neuraminidase 1 (NEU1), was regulated transcriptionally. NEU1 functions in complex with two other lysosomal hydrolases, β-galactosidase and cathepsin A (PPCA), and deficiency of NEU1 leads to sialidosis, a pediatric, neurosomatic LSD.…”

Organelle Cooperation in Stem Cell Fate: Lysosomes as Emerging Regulators of Cell Identity

“…Conversely, mTORC1 inhibits catabolic activities, predominantly lysosome biogenesis, and autophagy signaling. The primary catabolic targets include the autophagosome assembly protein ULK-1 and members of the TFE transcription factor family, key factors in the activation of lysosome biogenesis genes ( Sardiello et al, 2009 ; Palmieri et al, 2011 ; Settembre et al, 2011 ; Martina et al, 2014 ; Annunziata et al, 2019 ; Savini et al, 2019 ).…”