A G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma
Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of , results in genotype...
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| Veröffentlicht in: | CANCERS 2021-04, Vol.13 (8), p.1807 |
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| creator | Gamble, Laura D Purgato, Stefania Henderson, Michelle J Di Giacomo, Simone Russell, Amanda J Pigini, Paolo Murray, Jayne Valli, Emanuele Milazzo, Giorgio Giorgi, Federico M Cowley, Mark Ashton, Lesley J Bhalshankar, Jaydutt Schleiermacher, Gudrun Rihani, Ali Van Maerken, Tom Vandesompele, Jo Speleman, Frank Versteeg, Rogier Koster, Jan Eggert, Angelika Noguera, Rosa Stallings, Raymond L Tonini, Gian Paolo Fong, Kwun Vaksman, Zalman Diskin, Sharon J Maris, John M London, Wendy B Marshall, Glenn M Ziegler, David S Hogarty, Michael D Perini, Giovanni Norris, Murray D Haber, Michelle |
| description | Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of
, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype
-amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased
expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the
promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in
-amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the
G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein. |
| doi_str_mv | 10.3390/cancers13081807 |
| format | Article |
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, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype
-amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased
expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the
promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in
-amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the
G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers13081807</identifier><identifier>PMID: 33918978</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Acetylation ; Alleles ; C cells ; Cancer ; Cell growth ; Children ; Cloning ; Colorectal cancer ; CRISPR ; Enzymes ; Gene polymorphism ; Genetic diversity ; Genotype & phenotype ; Growth rate ; Histones ; Influence ; Medical prognosis ; Medicin och hälsovetenskap ; Neuroblastoma ; Neuroblastoma cells ; Ornithine decarboxylase ; Patients ; Polyamines ; Polymorphism ; Single-nucleotide polymorphism ; Transcription ; Transcription factors</subject><ispartof>CANCERS, 2021-04, Vol.13 (8), p.1807</ispartof><rights>2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2021 by the authors. 2021</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c509t-aa44654e438882bd621f37d8bcb5333603d0313d2b1cca8b665145c81e61e253</citedby><cites>FETCH-LOGICAL-c509t-aa44654e438882bd621f37d8bcb5333603d0313d2b1cca8b665145c81e61e253</cites><orcidid>0000-0003-4546-7459 ; 0000-0002-0632-4589 ; 0000-0001-7148-1081 ; 0000-0002-0890-7585 ; 0000-0002-9519-5714 ; 0000-0002-1930-4763 ; 0000-0001-6274-0184 ; 0000-0002-7325-9908 ; 0000-0002-0133-5879 ; 0000-0001-8496-9705 ; 0000-0003-4409-2421 ; 0000-0002-9221-4852 ; 0000-0002-1861-6570</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069650/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC8069650/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,552,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33918978$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttp://kipublications.ki.se/Default.aspx?queryparsed=id:146443592$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Gamble, Laura D</creatorcontrib><creatorcontrib>Purgato, Stefania</creatorcontrib><creatorcontrib>Henderson, Michelle J</creatorcontrib><creatorcontrib>Di Giacomo, Simone</creatorcontrib><creatorcontrib>Russell, Amanda J</creatorcontrib><creatorcontrib>Pigini, Paolo</creatorcontrib><creatorcontrib>Murray, Jayne</creatorcontrib><creatorcontrib>Valli, Emanuele</creatorcontrib><creatorcontrib>Milazzo, Giorgio</creatorcontrib><creatorcontrib>Giorgi, Federico M</creatorcontrib><creatorcontrib>Cowley, Mark</creatorcontrib><creatorcontrib>Ashton, Lesley J</creatorcontrib><creatorcontrib>Bhalshankar, Jaydutt</creatorcontrib><creatorcontrib>Schleiermacher, Gudrun</creatorcontrib><creatorcontrib>Rihani, Ali</creatorcontrib><creatorcontrib>Van Maerken, Tom</creatorcontrib><creatorcontrib>Vandesompele, Jo</creatorcontrib><creatorcontrib>Speleman, Frank</creatorcontrib><creatorcontrib>Versteeg, Rogier</creatorcontrib><creatorcontrib>Koster, Jan</creatorcontrib><creatorcontrib>Eggert, Angelika</creatorcontrib><creatorcontrib>Noguera, Rosa</creatorcontrib><creatorcontrib>Stallings, Raymond L</creatorcontrib><creatorcontrib>Tonini, Gian Paolo</creatorcontrib><creatorcontrib>Fong, Kwun</creatorcontrib><creatorcontrib>Vaksman, Zalman</creatorcontrib><creatorcontrib>Diskin, Sharon J</creatorcontrib><creatorcontrib>Maris, John M</creatorcontrib><creatorcontrib>London, Wendy B</creatorcontrib><creatorcontrib>Marshall, Glenn M</creatorcontrib><creatorcontrib>Ziegler, David S</creatorcontrib><creatorcontrib>Hogarty, Michael D</creatorcontrib><creatorcontrib>Perini, Giovanni</creatorcontrib><creatorcontrib>Norris, Murray D</creatorcontrib><creatorcontrib>Haber, Michelle</creatorcontrib><title>A G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma</title><title>CANCERS</title><addtitle>Cancers (Basel)</addtitle><description>Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of
, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype
-amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased
expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the
promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in
-amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the
G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein.</description><subject>Acetylation</subject><subject>Alleles</subject><subject>C cells</subject><subject>Cancer</subject><subject>Cell growth</subject><subject>Children</subject><subject>Cloning</subject><subject>Colorectal cancer</subject><subject>CRISPR</subject><subject>Enzymes</subject><subject>Gene polymorphism</subject><subject>Genetic diversity</subject><subject>Genotype & phenotype</subject><subject>Growth rate</subject><subject>Histones</subject><subject>Influence</subject><subject>Medical prognosis</subject><subject>Medicin och hälsovetenskap</subject><subject>Neuroblastoma</subject><subject>Neuroblastoma cells</subject><subject>Ornithine decarboxylase</subject><subject>Patients</subject><subject>Polyamines</subject><subject>Polymorphism</subject><subject>Single-nucleotide 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G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma</title><author>Gamble, Laura D ; Purgato, Stefania ; Henderson, Michelle J ; Di Giacomo, Simone ; Russell, Amanda J ; Pigini, Paolo ; Murray, Jayne ; Valli, Emanuele ; Milazzo, Giorgio ; Giorgi, Federico M ; Cowley, Mark ; Ashton, Lesley J ; Bhalshankar, Jaydutt ; Schleiermacher, Gudrun ; Rihani, Ali ; Van Maerken, Tom ; Vandesompele, Jo ; Speleman, Frank ; Versteeg, Rogier ; Koster, Jan ; Eggert, Angelika ; Noguera, Rosa ; Stallings, Raymond L ; Tonini, Gian Paolo ; Fong, Kwun ; Vaksman, Zalman ; Diskin, Sharon J ; Maris, John M ; London, Wendy B ; Marshall, Glenn M ; Ziegler, David S ; Hogarty, Michael D ; Perini, Giovanni ; Norris, Murray D ; Haber, 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Michelle</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>A G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma</atitle><jtitle>CANCERS</jtitle><addtitle>Cancers (Basel)</addtitle><date>2021-04-09</date><risdate>2021</risdate><volume>13</volume><issue>8</issue><spage>1807</spage><pages>1807-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><abstract>Ornithine decarboxylase (ODC1), a critical regulatory enzyme in polyamine biosynthesis, is a direct transcriptional target of MYCN, amplification of which is a powerful marker of aggressive neuroblastoma. A single nucleotide polymorphism (SNP), G316A, within the first intron of
, results in genotypes wildtype GG, and variants AG/AA. CRISPR-cas9 technology was used to investigate the effects of AG clones from wildtype
-amplified SK-N-BE(2)-C cells and the effect of the SNP on MYCN binding, and promoter activity was investigated using EMSA and luciferase assays. AG clones exhibited decreased
expression, growth rates, and histone acetylation and increased sensitivity to ODC1 inhibition. MYCN was a stronger transcriptional regulator of the
promoter containing the G allele, and preferentially bound the G allele over the A. Two neuroblastoma cohorts were used to investigate the clinical impact of the SNP. In the study cohort, the minor AA genotype was associated with improved survival, while poor prognosis was associated with the GG genotype and AG/GG genotypes in
-amplified and non-amplified patients, respectively. These effects were lost in the GWAS cohort. We have demonstrated that the
G316A polymorphism has functional significance in neuroblastoma and is subject to allele-specific regulation by the MYCN oncoprotein.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>33918978</pmid><doi>10.3390/cancers13081807</doi><orcidid>https://orcid.org/0000-0003-4546-7459</orcidid><orcidid>https://orcid.org/0000-0002-0632-4589</orcidid><orcidid>https://orcid.org/0000-0001-7148-1081</orcidid><orcidid>https://orcid.org/0000-0002-0890-7585</orcidid><orcidid>https://orcid.org/0000-0002-9519-5714</orcidid><orcidid>https://orcid.org/0000-0002-1930-4763</orcidid><orcidid>https://orcid.org/0000-0001-6274-0184</orcidid><orcidid>https://orcid.org/0000-0002-7325-9908</orcidid><orcidid>https://orcid.org/0000-0002-0133-5879</orcidid><orcidid>https://orcid.org/0000-0001-8496-9705</orcidid><orcidid>https://orcid.org/0000-0003-4409-2421</orcidid><orcidid>https://orcid.org/0000-0002-9221-4852</orcidid><orcidid>https://orcid.org/0000-0002-1861-6570</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 2072-6694 |
| ispartof | CANCERS, 2021-04, Vol.13 (8), p.1807 |
| issn | 2072-6694 2072-6694 |
| language | eng |
| recordid | cdi_swepub_primary_oai_swepub_ki_se_462431 |
| source | MDPI - Multidisciplinary Digital Publishing Institute; PubMed Central; SWEPUB Freely available online; EZB Electronic Journals Library; PubMed Central Open Access |
| subjects | Acetylation Alleles C cells Cancer Cell growth Children Cloning Colorectal cancer CRISPR Enzymes Gene polymorphism Genetic diversity Genotype & phenotype Growth rate Histones Influence Medical prognosis Medicin och hälsovetenskap Neuroblastoma Neuroblastoma cells Ornithine decarboxylase Patients Polyamines Polymorphism Single-nucleotide polymorphism Transcription Transcription factors |
| title | A G316A Polymorphism in the Ornithine Decarboxylase Gene Promoter Modulates MYCN-Driven Childhood Neuroblastoma |
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