Positive auto-regulation of MYCN in human neuroblastoma.
MYCN oncogene is one of the most important regulators affecting the prognosis of neuroblastoma and is frequently amplified in the high-risk subsets. Despite its clinical significance, it remains unclear how the MYCN expression is regulated in human neuroblastomas. Here, we found the presence of a positive auto-regulatory mechanism of MYCN. Enforced expression of MYCN induced endogenous MYCN mRNA expression in SK-N-AS neuroblastoma cells with a single copy of MYCN gene. Luciferase reporter assay revealed that MYCN protein activates its own promoter activity in a dose-dependent manner and the downstream region relative to the transcription start sites is responsible for the activation. Furthermore, ChIP analysis showed that MYCN is directly recruited onto the intron 1 region of MYCN gene which contains two putative E-box sites. Intriguingly, in response to all-trans-retinoic acid (ATRA), MYCN was down-regulated in MYCN-amplified SK-N-BE neuroblastoma cells, and the recruitment of MYCN protein onto its own intron 1 region was reduced in association with an induction of neuronal differentiation. Collectively, our present results suggest that MYCN contributes to its own expression by forming a positive auto-regulatory loop in neuroblastoma cells.
Suenaga
Yusuke
Y
Division of Biochemistry and Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Nitona, Chiba 260-8717, Japan.
Kaneko
Yoshiki
Y
Matsumoto
Daisuke
D
Hossain
Mohammad Shamim
MS
Ozaki
Toshinori
T
Nakagawara
Akira
A
D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D024721:E-Box Elements; D005786:Gene Expression Regulation; D015894:Genome, Human / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000378:metabolism*; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000166:cytology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology
C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D012333:RNA, Messenger; D014212:Tretinoin