Positive auto-regulation of MYCN in human neuroblastoma

Suenaga, Yusuke; Kaneko, Yoshiki; Matsumoto, Daisuke; Hossain, Shamim; Ozaki, Toshinori; Nakagawara, Akira

doi:10.1016/j.bbrc.2009.09.044

Cited by 27 publications

(25 citation statements)

References 29 publications

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“…Previously we have reported that MYCN directly targets its own expression in neuroblastoma cell lines [27]. Because the promoter region of the NCYM gene is localized within intron 1 of MYCN (Figure S9A), we examined whether MYCN regulates NCYM transcription.…”

Section: Resultsmentioning

confidence: 99%

“…We previously made a MYCN-luc (+1312) plasmid that contains the region of MYCN promoter region spanning from −221 to +1312 (where +1 represents the transcription start site) [27]. Luciferase reporter plasmids containing different lengths of the MYCN promoter were generated from MYCN-Luc (+1312) by partial removals of the MYCN promoter region with appropriate restriction enzymes.…”

Section: Methodsmentioning

confidence: 99%

“…(A) The NCYM promoter sequence. The sequences of primer sets used in our previous report [27] are shown as MYCN ChIP Forward (Reverse) Primer. The recruitment of the MYCN protein to its own intron 1 was detected using those primers.…”

Section: Supporting Informationmentioning

confidence: 99%

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NCYM, a Cis-Antisense Gene of MYCN, Encodes a De Novo Evolved Protein That Inhibits GSK3β Resulting in the Stabilization of MYCN in Human Neuroblastomas

et al. 2014

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The rearrangement of pre-existing genes has long been thought of as the major mode of new gene generation. Recently, de novo gene birth from non-genic DNA was found to be an alternative mechanism to generate novel protein-coding genes. However, its functional role in human disease remains largely unknown. Here we show that NCYM, a cis-antisense gene of the MYCN oncogene, initially thought to be a large non-coding RNA, encodes a de novo evolved protein regulating the pathogenesis of human cancers, particularly neuroblastoma. The NCYM gene is evolutionally conserved only in the taxonomic group containing humans and chimpanzees. In primary human neuroblastomas, NCYM is 100% co-amplified and co-expressed with MYCN, and NCYM mRNA expression is associated with poor clinical outcome. MYCN directly transactivates both NCYM and MYCN mRNA, whereas NCYM stabilizes MYCN protein by inhibiting the activity of GSK3β, a kinase that promotes MYCN degradation. In contrast to MYCN transgenic mice, neuroblastomas in MYCN/NCYM double transgenic mice were frequently accompanied by distant metastases, behavior reminiscent of human neuroblastomas with MYCN amplification. The NCYM protein also interacts with GSK3β, thereby stabilizing the MYCN protein in the tumors of the MYCN/NCYM double transgenic mice. Thus, these results suggest that GSK3β inhibition by NCYM stabilizes the MYCN protein both in vitro and in vivo. Furthermore, the survival of MYCN transgenic mice bearing neuroblastoma was improved by treatment with NVP-BEZ235, a dual PI3K/mTOR inhibitor shown to destabilize MYCN via GSK3β activation. In contrast, tumors caused in MYCN/NCYM double transgenic mice showed chemo-resistance to the drug. Collectively, our results show that NCYM is the first de novo evolved protein known to act as an oncopromoting factor in human cancer, and suggest that de novo evolved proteins may functionally characterize human disease.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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NCYM, a Cis-Antisense Gene of MYCN, Encodes a De Novo Evolved Protein That Inhibits GSK3β Resulting in the Stabilization of MYCN in Human Neuroblastomas

et al. 2014

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“…NCYM stabilizes MYCN through inhibition of GSK3b, and MYCN stimulates NCYM transcription [8]. MYCN amplification in human neuroblastomas induces both MYCN and NCYM, and the positive auto-regulatory loop between MYCN and NCYM keeps their expression at high levels [8,12]. Furthermore, overexpression of MYCN and NCYM in the sympathetic nervous system of mice frequently develops metastatic tumors, inhibiting apoptotic cell death within the tumors [8]; however the molecular mechanisms by which NCYM regulates cell survival have remained elusive.…”

Section: Introductionmentioning

confidence: 97%

NCYM promotes calpain-mediated Myc-nick production in human MYCN-amplified neuroblastoma cells

Watanabe

Suenaga

Kaneko

et al. 2015

Biochemical and Biophysical Research Communications

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NCYM is a cis-antisense gene of MYCN and is amplified in human neuroblastomas. High NCYM expression is associated with poor prognoses, and the NCYM protein stabilizes MYCN to promote proliferation of neuroblastoma cells. However, the molecular mechanisms of NCYM in the regulation of cell survival have remained poorly characterized. Here we show that NCYM promotes cleavage of MYCN to produce the anti-apoptotic protein, Myc-nick, both in vitro and in vivo. NCYM and Myc-nick were induced at G2/M phase, and NCYM knockdown induced apoptotic cell death accompanied by Myc-nick downregulation. These results reveal a novel function of NCYM as a regulator of Myc-nick production in human neuroblastomas.

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“…It is generally accepted that the amplification of the MYCN proto-oncogene is highly relevant to the genesis and prognosis of neuroblastoma [3,4]. MYCN is an important member of the myc family that includes 3 strong oncogenes, MYC, MYCN, and MYCL [5].…”

Section: Introductionmentioning

confidence: 99%

Target delivery of MYCN siRNA by folate-nanoliposomes delivery system in a metastatic neuroblastoma model

et al. 2013

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BackgroundFolate-nanoliposomes delivery system has emerged recently as a specific and safety delivery method and gradually used as the carrier of a variety kinds of drugs including compounds, plasmids and siRNAs.MethodsIn this study, we established a bone marrow and bone metastasis xenograft mouse model by injecting the LA-N-5 cell into the bone marrow cavity. Fluorescence microscopy, TUNEL Assay, Quantitative RT-PCR and western blot were conducted to analysis the distribution of folate-nanoliposomes entrapped MYCN (V-myc myelocytomatosis viral related oncogene) siRNA in mice and the relevant suppression effect.ResultsThe folate-nanoliposomes entrapped MYCN siRNA can be specifically distributed in tumor tissues. Further study shows that folate-nanoliposomes entrapped MYCN siRNA lead to MYCN mRNA expression significantly down-regulated (>50%, and p < 0.05) compared with negative control siRNA treatment. MYCN protein expression was inhibited about 60% in vivo, thus induced tumor cell apoptosis markedly.ConclusionThis study point to a new way for treatment of metastatic neuroblastoma and could widen the application of folate-nanoliposomes delivery system in tumor therapy.

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Positive auto-regulation of MYCN in human neuroblastoma

Cited by 27 publications

References 29 publications

NCYM, a Cis-Antisense Gene of MYCN, Encodes a De Novo Evolved Protein That Inhibits GSK3β Resulting in the Stabilization of MYCN in Human Neuroblastomas

NCYM, a Cis-Antisense Gene of MYCN, Encodes a De Novo Evolved Protein That Inhibits GSK3β Resulting in the Stabilization of MYCN in Human Neuroblastomas

NCYM promotes calpain-mediated Myc-nick production in human MYCN-amplified neuroblastoma cells

Target delivery of MYCN siRNA by folate-nanoliposomes delivery system in a metastatic neuroblastoma model

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