Lysine-specific demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma

Amente, Stefano; Milazzo, Giorgio; Sorrentino, Maria Cristina; Ambrosio, Susanna; Palo, Giacomo Di; Lania, Luigi; Perini, Giovanni; Majello, Barbara

doi:10.18632/oncotarget.3990

Cited by 50 publications

(63 citation statements)

References 41 publications

(56 reference statements)

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“…One recent study showed that c-Myc interacts with histone demethylases KDM4B and KDM4C to regulate mouse embryonic cell stemness (36). The histone demethylase KDM1A has been shown to reprogram the transcriptome of neuroblastoma cells and regulates neuroblastoma xenograft growth (37), cooperating with N-Myc to repress tumor suppressor genes in neuroblastoma (38). We have recently identified that KDM4B physically interacts with N-Myc and maintains the low levels of repressive H3K9me3/me2 marks at Myc target gene loci in neuroblastoma, thereby facilitating N-Myc activity (14).…”

Section: Discussionmentioning

confidence: 99%

Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox

Yang

Milasta

et al. 2017

Cancer Research

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Histone lysine demethylases facilitate the activity of oncogenic transcription factors including possibly MYC. Here we show that multiple histone demethylases influence the viability and poor prognosis of neuroblastoma cells where MYC is often overexpressed. We also identified the approved small molecule antifungal agent ciclopirox as a novel pan-histone demethylase inhibitor. Ciclopirox targeted several histone demethylases including KDM4B implicated in MYC function. Accordingly, ciclopirox inhibited Myc signaling in parallel with mitochondrial oxidative phosphorylation, resulting in suppression of neuroblastoma cell viability and inhibition of tumor growth associated with an induction of differentiation. Our findings provide new insights into epigenetic regulation of MYC function and suggest a novel pharmacologic basis to target histone demethylases as an indirect MYC targeting approach for cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox

Yang

Milasta

et al. 2017

Cancer Research

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“…We recently showed that MYCN interacts with LSD1 and that the LSD1/MYCN complex controls transcription of tumor suppressor genes such as p21 and CLU [6]. Moreover LSD1 inhibition results in cell growth arrest of cultured NB cells.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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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.

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“…Despite concerted worldwide efforts to tackle glioblastoma, patient prognosis remains grim and recurrence is inevitable (Rich, ; Stupp et al ., ). Several histone demethylases, including LSD1, KDM5A, and KDM5B, are upregulated in malignant gliomas, sustaining cell growth, and resistance to chemotherapy (Amente et al ., ; Banelli et al ., ; Black et al ., ; Dai et al ., ; Hayami et al ., ; Tzatsos et al ., ). In the present study, we examined the role of KDM2B in glioblastoma.…”

Section: Discussionmentioning

confidence: 98%

Targeting glioma stem‐like cell survival and chemoresistance through inhibition of lysine‐specific histone demethylase KDM2B

et al. 2018

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Glioblastoma (GBM) ranks among the most lethal cancers, with current therapies offering only palliation. Inter‐ and intrapatient heterogeneity is a hallmark of GBM, with epigenetically distinct cancer stem‐like cells (CSCs) at the apex. Targeting GSCs remains a challenging task because of their unique biology, resemblance to normal neural stem/progenitor cells, and resistance to standard cytotoxic therapy. Here, we find that the chromatin regulator, JmjC domain histone H3K36me2/me1 demethylase KDM2B, is highly expressed in glioblastoma surgical specimens compared to normal brain. Targeting KDM2B function genetically or pharmacologically impaired the survival of patient‐derived primary glioblastoma cells through the induction of DNA damage and apoptosis, sensitizing them to chemotherapy. KDM2B loss decreased the GSC pool, which was potentiated by coadministration of chemotherapy. Collectively, our results demonstrate KDM2B is crucial for glioblastoma maintenance, with inhibition causing loss of GSC survival, genomic stability, and chemoresistance.

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Lysine-specific demethylase (LSD1/KDM1A) and MYCN cooperatively repress tumor suppressor genes in neuroblastoma

Cited by 50 publications

References 41 publications

Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox

Targeting Histone Demethylases in MYC-Driven Neuroblastomas with Ciclopirox

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

Targeting glioma stem‐like cell survival and chemoresistance through inhibition of lysine‐specific histone demethylase KDM2B

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