Oncogenic Orphan Nuclear Receptor NR4A3 Interacts and Cooperates with MYB in Acinic Cell Carcinoma
Acinic cell carcinoma (AcCC) is a morphologically distinctive salivary gland malignancy often associated with chromosome rearrangements leading to overexpression of the NR4A3 transcription factor. However, little is known about how NR4A3 contributes to AcCC biology. Detailed RNA-sequencing of 21 arc...
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| Veröffentlicht in: | Cancers 2020-08, Vol.12 (9), p.2433 |
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| creator | Lee, David Y Brayer, Kathryn J Mitani, Yoshitsugu Burns, Eric A Rao, Pulivarthi H Bell, Diana Williams, Michelle D Ferrarotto, Renata Pytynia, Kristen B El-Naggar, Adel K Ness, Scott A |
| description | Acinic cell carcinoma (AcCC) is a morphologically distinctive salivary gland malignancy often associated with chromosome rearrangements leading to overexpression of the NR4A3 transcription factor. However, little is known about how NR4A3 contributes to AcCC biology. Detailed RNA-sequencing of 21 archived AcCC samples revealed fusion reads arising from recurrent t(4;9), t(9;12), t(8;9) or t(2;4) chromosomal translocations, which positioned highly active enhancers adjacent to the promoter of the
gene or the closely related
gene, resulting in their aberrant overexpression. Transcriptome analyses revealed several distinct subgroups of AcCC tumors, including a subgroup that overexpressed both
and
. A poor survival subset of the tumors with high-grade transformation expressed
and
as well as
, an oncogene that is the major driver in a different type of salivary gland tumor, adenoid cystic carcinoma. The combination of
and
showed cooperativity in regulating a distinct set of genes. In addition, the ligand binding domain of NR4A3 directly bound the Myb DNA binding domain. Transformation assays indicated that, while overexpressed NR4A3 was sufficient to generate transformed colonies, the combination of NR4A3 plus Myb was more potent, leading to anchorage-independent growth and increased cellular invasiveness. The results confirm that
and
are the main driver genes of AcCC and suggest that concurrent overexpression of
and
defines a subset of AcCC patients with high-grade transformation that display exceptionally poor outcome. |
| doi_str_mv | 10.3390/cancers12092433 |
| format | Article |
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gene or the closely related
gene, resulting in their aberrant overexpression. Transcriptome analyses revealed several distinct subgroups of AcCC tumors, including a subgroup that overexpressed both
and
. A poor survival subset of the tumors with high-grade transformation expressed
and
as well as
, an oncogene that is the major driver in a different type of salivary gland tumor, adenoid cystic carcinoma. The combination of
and
showed cooperativity in regulating a distinct set of genes. In addition, the ligand binding domain of NR4A3 directly bound the Myb DNA binding domain. Transformation assays indicated that, while overexpressed NR4A3 was sufficient to generate transformed colonies, the combination of NR4A3 plus Myb was more potent, leading to anchorage-independent growth and increased cellular invasiveness. The results confirm that
and
are the main driver genes of AcCC and suggest that concurrent overexpression of
and
defines a subset of AcCC patients with high-grade transformation that display exceptionally poor outcome.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12092433</identifier><identifier>PMID: 32867110</identifier><language>eng</language><publisher>Switzerland: MDPI AG</publisher><subject>Adenoid ; Artificial chromosomes ; Chromosome rearrangements ; Chromosome translocations ; Cloning ; Enhancers ; Gene expression ; Genetic transformation ; Genomics ; Health aspects ; Hybridization ; Invasiveness ; Lymphatic system ; Malignancy ; Proopiomelanocortin ; Proteins ; Ribonucleic acid ; RNA ; Salivary gland ; Salivary gland tumors ; Transcription factors ; Tumors</subject><ispartof>Cancers, 2020-08, Vol.12 (9), p.2433</ispartof><rights>COPYRIGHT 2020 MDPI AG</rights><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c449t-72b9c6d0d7dbe18f7fe6f0d1ea2a6b4552af40c7ebded48e51bad8d61b4479d13</citedby><cites>FETCH-LOGICAL-c449t-72b9c6d0d7dbe18f7fe6f0d1ea2a6b4552af40c7ebded48e51bad8d61b4479d13</cites><orcidid>0000-0002-1625-2400 ; 0000-0002-8661-4702 ; 0000-0001-6965-8909</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/PMC7565926/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7565926/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27922,27923,53789,53791</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32867110$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lee, David Y</creatorcontrib><creatorcontrib>Brayer, Kathryn J</creatorcontrib><creatorcontrib>Mitani, Yoshitsugu</creatorcontrib><creatorcontrib>Burns, Eric A</creatorcontrib><creatorcontrib>Rao, Pulivarthi H</creatorcontrib><creatorcontrib>Bell, Diana</creatorcontrib><creatorcontrib>Williams, Michelle D</creatorcontrib><creatorcontrib>Ferrarotto, Renata</creatorcontrib><creatorcontrib>Pytynia, Kristen B</creatorcontrib><creatorcontrib>El-Naggar, Adel K</creatorcontrib><creatorcontrib>Ness, Scott A</creatorcontrib><title>Oncogenic Orphan Nuclear Receptor NR4A3 Interacts and Cooperates with MYB in Acinic Cell Carcinoma</title><title>Cancers</title><addtitle>Cancers (Basel)</addtitle><description>Acinic cell carcinoma (AcCC) is a morphologically distinctive salivary gland malignancy often associated with chromosome rearrangements leading to overexpression of the NR4A3 transcription factor. However, little is known about how NR4A3 contributes to AcCC biology. Detailed RNA-sequencing of 21 archived AcCC samples revealed fusion reads arising from recurrent t(4;9), t(9;12), t(8;9) or t(2;4) chromosomal translocations, which positioned highly active enhancers adjacent to the promoter of the
gene or the closely related
gene, resulting in their aberrant overexpression. Transcriptome analyses revealed several distinct subgroups of AcCC tumors, including a subgroup that overexpressed both
and
. A poor survival subset of the tumors with high-grade transformation expressed
and
as well as
, an oncogene that is the major driver in a different type of salivary gland tumor, adenoid cystic carcinoma. The combination of
and
showed cooperativity in regulating a distinct set of genes. In addition, the ligand binding domain of NR4A3 directly bound the Myb DNA binding domain. Transformation assays indicated that, while overexpressed NR4A3 was sufficient to generate transformed colonies, the combination of NR4A3 plus Myb was more potent, leading to anchorage-independent growth and increased cellular invasiveness. The results confirm that
and
are the main driver genes of AcCC and suggest that concurrent overexpression of
and
defines a subset of AcCC patients with high-grade transformation that display exceptionally poor outcome.</description><subject>Adenoid</subject><subject>Artificial chromosomes</subject><subject>Chromosome rearrangements</subject><subject>Chromosome translocations</subject><subject>Cloning</subject><subject>Enhancers</subject><subject>Gene expression</subject><subject>Genetic transformation</subject><subject>Genomics</subject><subject>Health aspects</subject><subject>Hybridization</subject><subject>Invasiveness</subject><subject>Lymphatic system</subject><subject>Malignancy</subject><subject>Proopiomelanocortin</subject><subject>Proteins</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Salivary gland</subject><subject>Salivary gland tumors</subject><subject>Transcription factors</subject><subject>Tumors</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1vFSEUxYnR2KZ27c6QuHHzLF8Dw8bkOfGjSe1LGl24IgzceY9mHowwU-N_L8_WWsvmcnN_HDgchF5S8pZzTc6cjQ5yoYxoJjh_go4ZUWwlpRZPH-yP0Gkp16QuzqmS6jk64qyVilJyjPpNdGkLMTi8ydPORny5uBFsxlfgYJpTxpdXYs3xeZwhWzcXbKPHXUpTbWco-GeYd_jL9_c4RLx24aDUwTjizubapb19gZ4NdixweldP0LePH752n1cXm0_n3fpi5YTQ80qxXjvpiVe-B9oOagA5EE_BMit70TTMDoI4Bb0HL1poaG996yXthVDaU36C3t3qTku_B-8gztmOZsphb_Mvk2ww_09i2JltujGqkY1msgq8uRPI6ccCZTb7UFz1YiOkpZj6yVpWTpKKvn6EXqclx2rvD0VaSWnzj9raEUyIQ6r3uoOoWUve0lZroip1dku5nErJMNw_mRJzCNo8CrqeePXQ6T3_N1b-Gw_VpJ0</recordid><startdate>20200827</startdate><enddate>20200827</enddate><creator>Lee, David Y</creator><creator>Brayer, Kathryn J</creator><creator>Mitani, Yoshitsugu</creator><creator>Burns, Eric A</creator><creator>Rao, Pulivarthi H</creator><creator>Bell, Diana</creator><creator>Williams, Michelle D</creator><creator>Ferrarotto, Renata</creator><creator>Pytynia, Kristen B</creator><creator>El-Naggar, Adel K</creator><creator>Ness, Scott A</creator><general>MDPI AG</general><general>MDPI</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7T5</scope><scope>7TO</scope><scope>7XB</scope><scope>8FE</scope><scope>8FH</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>LK8</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-1625-2400</orcidid><orcidid>https://orcid.org/0000-0002-8661-4702</orcidid><orcidid>https://orcid.org/0000-0001-6965-8909</orcidid></search><sort><creationdate>20200827</creationdate><title>Oncogenic Orphan Nuclear Receptor NR4A3 Interacts and Cooperates with MYB in Acinic Cell Carcinoma</title><author>Lee, David Y ; 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However, little is known about how NR4A3 contributes to AcCC biology. Detailed RNA-sequencing of 21 archived AcCC samples revealed fusion reads arising from recurrent t(4;9), t(9;12), t(8;9) or t(2;4) chromosomal translocations, which positioned highly active enhancers adjacent to the promoter of the
gene or the closely related
gene, resulting in their aberrant overexpression. Transcriptome analyses revealed several distinct subgroups of AcCC tumors, including a subgroup that overexpressed both
and
. A poor survival subset of the tumors with high-grade transformation expressed
and
as well as
, an oncogene that is the major driver in a different type of salivary gland tumor, adenoid cystic carcinoma. The combination of
and
showed cooperativity in regulating a distinct set of genes. In addition, the ligand binding domain of NR4A3 directly bound the Myb DNA binding domain. Transformation assays indicated that, while overexpressed NR4A3 was sufficient to generate transformed colonies, the combination of NR4A3 plus Myb was more potent, leading to anchorage-independent growth and increased cellular invasiveness. The results confirm that
and
are the main driver genes of AcCC and suggest that concurrent overexpression of
and
defines a subset of AcCC patients with high-grade transformation that display exceptionally poor outcome.</abstract><cop>Switzerland</cop><pub>MDPI AG</pub><pmid>32867110</pmid><doi>10.3390/cancers12092433</doi><orcidid>https://orcid.org/0000-0002-1625-2400</orcidid><orcidid>https://orcid.org/0000-0002-8661-4702</orcidid><orcidid>https://orcid.org/0000-0001-6965-8909</orcidid><oa>free_for_read</oa></addata></record> |
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| source | PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Adenoid Artificial chromosomes Chromosome rearrangements Chromosome translocations Cloning Enhancers Gene expression Genetic transformation Genomics Health aspects Hybridization Invasiveness Lymphatic system Malignancy Proopiomelanocortin Proteins Ribonucleic acid RNA Salivary gland Salivary gland tumors Transcription factors Tumors |
| title | Oncogenic Orphan Nuclear Receptor NR4A3 Interacts and Cooperates with MYB in Acinic Cell Carcinoma |
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