The histone demethylase JMJD1A induces cell migration and invasion by up-regulating the expression of the long noncoding RNA MALAT1
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Andrew E. Tee1, Dora Ling1, Charlotte Nelson1, Bernard Atmadibrata1, Marcel E. Dinger2, Ning Xu1, Tamio Mizukami3, Pei Y. Liu1, Bing Liu1, Belamy Cheung1, Eddy Pasquier1,4, Michelle Haber1, Murray D. Norris1, Takayoshi Suzuki5, Glenn M. Marshall1,6 and Tao Liu1,7
1 Children’s Cancer Institute Australia for Medical Research, Randwick, Sydney, Australia
2 Garvan Institute of Medical Research, Darlinghurst, Sydney, Australia
3 Graduate School of Bio-Science, Nagahama Institute of Bio-Science and Technology, Nagahama, Shiga, Japan
4 Metronomics Global Health Initiative, Marseille, France
5 Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Taishogun Nishitakatsukasa-Cho, Kita-ku, Kyoto, Japan
6 Kids Cancer Centre, Sydney Children’s Hospital, Randwick, , Australia
7 School of Women’s & Children’s Health, UNSW Medicine, University of New South Wales, Randwick, Sydney, Australia
Tao Liu, email:
Keywords: neuroblastoma, N-Myc, JMJD1A, histone demethylation, MALAT1
Received: January 3, 2014 Accepted: February 16, 2014 Published: February 18, 2014
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.
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