Abstract
Patients with neuroblastoma due to N-Myc oncogene amplification have a high frequency of tumor metastasis. However, it is not clear how N-Myc induces cell migration, invasion and metastasis. The histone demethylase JMJD1A activates gene transcription by demethylating the lysine 9 residue of histone H3 (H3K9) at target gene promoters. The long noncoding RNA MALAT1 induces lung cancer cell migration and plays a pivotal role in lung cancer metastasis. Here we demonstrated that N-Myc up-regulated the expression of JMJD1A in N-Myc oncogene-amplified human neuroblastoma cells by directly binding to the JMJD1A gene promoter. Affymetrix microarray studies revealed that the gene second most significantly up-regulated by JMJD1A was MALAT1. Consistent with this finding, RT-PCR and chromatin immunoprecipitation assays showed that JMJD1A bound to the MALAT1 gene promoter and demethylated histone H3K9 at the MALAT1 gene promoter. Moreover, JMJD1A and MALAT1 induced, while the small molecule JMJD1A inhibitor DMOG suppressed, neuroblastoma cell migration and invasion. Taken together, our data identify a novel pathway through which N-Myc causes neuroblastoma cell migration and invasion, and provide important evidence for further development of more potent JMJD1A/MALAT1 inhibitors for the prevention of tumor metastasis.
Highlights
Neuroblastoma, which originates from precursor neuroblast cells in the sympathetic nervous systems, is the most common extracranial solid tumor in children
JMJD1A gene expression is down-regulated by the microRNA mir-155 [15], and up-regulated by hypoxiainducible factor 1α (HIF1α), hypoxia, starvation and iron scavengers in tumor tissues [16,17,18,19,20]
We have identified a canonical Mycresponsive element E-Box at the JMJD1A gene core promoter, and found that c-Myc oncoprotein binds to JMJD1A gene core promoter encompassing the E-Box in a publicly available ChIP-Seq dataset
Summary
Neuroblastoma, which originates from precursor neuroblast cells in the sympathetic nervous systems, is the most common extracranial solid tumor in children. Myc oncoproteins, including N-Myc and c-Myc, induce malignant transformation and tumor progression by directly binding to cognate DNA sequences and modulating gene transcription [3, 4]. Myc oncoproteins activate gene transcription by directly binding to Mycresponsive element E-Boxes at target gene promoters. Gene transcription is a dynamic process, during www.impactjournals.com/oncotarget which lysine residues of histone H3 are modified by histone demethylases and methyltransferases to change RNA polymerase’s ability to access the transcription start site [5, 6]. Many lines of evidence suggest that demethylation of repressive histone methylation marks such as histone H3 lysine 9 (H3K9) by histone demethylases is a prerequisite for transcriptional activation by transcription factors [7,8,9]
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