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MYCN Amplification ...
MYCN Amplification Is Associated with Reduced Expression of Genes Encoding gamma-Secretase Complex and NOTCH Signaling Components in Neuroblastoma
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- Agarwal, Prasoon (författare)
- Lund Univ, Dept Lab Med, Div Occupat & Environm Med, Sci Life Lab,Natl Bioinformat Infrastructure Swede, S-22362 Lund, Sweden.
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- Glowacka, Aleksandra (författare)
- Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17165 Solna, Sweden.
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- Mahmoud, Loay (författare)
- Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden.
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- Bazzar, Wesam (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17165 Solna, Sweden.
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- Larsson, Lars-Gunnar, 1947- (författare)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17165 Solna, Sweden.
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- Alzrigat, Mohammad (författare)
- Uppsala universitet,Science for Life Laboratory, SciLifeLab,Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17165 Solna, Sweden.
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Lund Univ, Dept Lab Med, Div Occupat & Environm Med, Sci Life Lab,Natl Bioinformat Infrastructure Swede, S-22362 Lund, Sweden Karolinska Inst, Dept Microbiol Tumor & Cell Biol, S-17165 Solna, Sweden. (creator_code:org_t)
- MDPI, 2023
- 2023
- Engelska.
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Ingår i: International Journal of Molecular Sciences. - : MDPI. - 1661-6596 .- 1422-0067. ; 24:9
- Relaterad länk:
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https://uu.diva-port... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.3...
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Abstract
Ämnesord
Stäng
- Amplification of the MYCN oncogene is found in similar to 20% of neuroblastoma (NB) cases and correlates with high-risk disease and poor prognosis. Despite the plethora of studies describing the role of MYCN in NB, the exact molecular mechanisms underlying MYCN's contribution to high-risk disease are not completely understood. Herein, we implemented an integrative approach combining publicly available RNA-Seq and MYCN ChIP-Seq datasets derived from human NB cell lines to define biological processes directly regulated by MYCN in NB. Our approach revealed that MYCN-amplified NB cell lines, when compared to non-MYCN-amplified cell lines, are characterized by reduced expression of genes involved in NOTCH receptor processing, axoneme assembly, and membrane protein proteolysis. More specifically, we found genes encoding members of the gamma-secretase complex, which is known for its ability to liberate several intracellular signaling molecules from membrane-bound proteins such as NOTCH receptors, to be down-regulated in MYCN-amplified NB cell lines. Analysis of MYCN ChIP-Seq data revealed an enrichment of MYCN binding at the transcription start sites of genes encoding gamma-secretase complex subunits. Notably, using publicly available gene expression data from NB primary tumors, we revealed that the expression of gamma-secretase subunits encoding genes and other components of the NOTCH signaling pathway was also reduced in MYCN-amplified tumors and correlated with worse overall survival in NB patients. Genetic or pharmacological depletion of MYCN in NB cell lines induced the expression of gamma-secretase genes and NOTCH-target genes. Chemical inhibition of gamma-secretase activity dampened the expression of NOTCH-target genes upon MYCN depletion in NB cells. In conclusion, this study defines a set of MYCN-regulated pathways that are specific to MYCN-amplified NB tumors, and it suggests a novel role for MYCN in the suppression of genes of the gamma-secretase complex, with an impact on the NOTCH-target gene expression in MYCN-amplified NB.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Nyckelord
- neuroblastoma
- MYCN amplification
- MYCN
- gamma-secretase
- NOTCH signaling
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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