Open AccessMYCN is a novel oncogenic target in adult B‐ ALL that activates the Wnt/β‐catenin pathway by suppressing DKK 3
Author(s) -
Kong Desheng,
Zhao Linlin,
Sun Lili,
Fan Shengjin,
Li Huibo,
Zhao Yanqiu,
Guo Zhibo,
Lin Leilei,
Cui Lin,
Wang Ke,
Chen Wenjia,
Zhang Yihui,
Zhou Jin,
Li Yinghua
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13644
Subject(s) - demethylating agent , wnt signaling pathway , gene knockdown , gene silencing , cancer research , methylation , biology , luciferase , dna methylation , cell growth , apoptosis , chemistry , microbiology and biotechnology , gene , signal transduction , gene expression , genetics , transfection
Dickkopf‐3 ( DKK 3 ) is frequently down‐regulated by promoter hypermethylation and is closely associated with a poor prognosis in many cancers. Our previous studies have shown that miR‐708 down‐regulates DKK 3 at the post‐transcriptional level in B‐ ALL . However, whether transcriptional mechanisms lead to DKK 3 silencing remains unclear. Here, we analysed the promoter regions of DKK 3 by bioinformatics and found binding sites for MYCN . A dual‐luciferase reporter gene assay and Ch IP experiments revealed that MYCN negatively regulates DKK 3 at the transcriptional level in B‐ ALL cell lines, and using bisulphite sequencing PCR , we affirmed that MYCN has no effect on the methylation of the DKK 3 promoter. MYCN silencing in B‐ ALL cells resulted in reduced cell proliferation, increased apoptosis and G1 phase arrest. Treatment with MYCN si RNA or 5‐aza‐2′‐deoxycytidine (5‐AdC), a demethylating agent, significantly increased the levels of DKK 3 mRNA and protein and decreased the protein levels of p‐ GSK 3β and nuclear β‐catenin, which indicates inhibition of the Wnt/β‐catenin pathway in vitro. MYCN knockdown significantly decreased the tumorigenic capacity of Nalm6 cells, which restored DKK 3 levels and inhibited the Wnt/β‐catenin pathway in vivo. Our study provides an increased understanding of adult B‐ ALL pathogenesis, which may be beneficial to the development of effective prognostic markers or therapeutic targets.