LSD1 mediates MYCN control of epithelial-mesenchymal transition through silencing of metastatic suppressor NDRG1 gene

Abstract

Neuroblastoma (NB) with MYCN amplification is a highly aggressive and metastatic tumor in children. The high recurrence rate and resistance of NB cells to drugs urgently demands a better therapy for this disease. We have recently found that MYCN interacts with the lysine-specific demethylase 1 (LSD1), a histone modifier that participates in key aspects of gene transcription. In cancer cells, LSD1 contributes to the genetic reprogramming that underlies to Epithelial-Mesenchymal Transition (EMT) and tumor metastasis. Here, we show that LSD1 affects motility and invasiveness of NB cells by modulating the transcription of the metastasis suppressor NDRG1 (N-Myc Downstream-Regulated Gene 1). At mechanistic level, we found that LSD1 co-localizes with MYCN at the promoter region of the NDRG1 gene and inhibits its expression. Pharmacological inhibition of LSD1 relieves repression of NDRG1 by MYCN and affects motility and invasiveness of NB cells. These effects were reversed by overexpressing NDRG1. In NB tissues, high levels of LSD1 correlate with low levels of NDRG1 and reduced patients survival. Collectively, our findings elucidate a mechanism of how MYCN/LSD1 control motility and invasiveness of NB cells through transcription regulation of NDRG1 expression and suggest that pharmacological targeting of LSD1 represents a valuable approach for NB therapy.

A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Periplaques of Spinal Cords from Progressive Multiple Sclerosis Patients

“…Again, we used bioinformatics tools to explore such putative links and performed a meta-analysis of the protein interactants potentially linking the identified candidate cytokines with N-Myc. Indeed, a well identified mechanism of NDRG1 repression relies on the binding of N-Myc to the promoter region of NDRG1 and the subsequent recruitment of histone deacetylases leading to promoter hypermethylation and an epigenetic silencing of NDRG1 [47][48][49][50][51][52]. Our meta-analysis showed that only TGFBR1 (an oligodendrocyte-expressed receptor to TGFB1) and PDGRA (an oligodendrocyte-expressed receptor to PDGFC) formed a close (second shell) protein network with N-MyC.…”

“…Since then, in multiple cell types, MYCN was shown to silence NDRG1 gene expression via a process involving a hypermethylation of the NDRG1 promoter [47][48][49][50][51][52] . On this basis, we performed a meta-analysis of the human interactome to determine whether signaling pathways could link MYCN to the identified candidate molecules (i.e IL17D, IL33, IL12A, PDGF-C and TGFB1).…”

Preclinical studies reveal that LSD1 inhibition results in tumor growth arrest in lung adenocarcinoma independently of driver mutations

“…Additionally, we observed that the half‐life of LSD1 is decreased from an initial 30 h to 21 h after HCI‐2509 treatment. This is in agreement with previous studies with respect to neuroblastoma and prostate cancer (Ambrosio et al ., ; Sehrawat et al ., ).…”

Endogenously generated DNA nucleobase modifications source, and significance as possible biomarkers of malignant transformation risk, and role in anticancer therapy

“…There is evidence that demonstrates that 8-oxoGua generation may regulate transcriptional activation, derived from experiments involving estrogen-responsive genes, Myc targeted genes and hypoxia-inducible genes [48][49][50][51]. It was demonstrated that exposure of cells to estrogen substantially increases 8-oxoGua in the promoter region of estrogen-responsive genes, which in turn recruits OGG1 and topoisomerase IIβ.…”

“…OGG1 generates transient nicks, which allows entry of the topoisomerase, the activity of which relaxes the DNA strand, triggering chromatin conformational changes essential for estrogen-induced transcription [48]. It has been shown that a similar mechanism is responsible for Myc-induced transcription activation [50]. It is proposed that upon binding of above mentioned transcription factors to the specific sequences, demethylating enzyme lysine-specific demethylase 1 (LSD1) is recruiting.…”