Publication Date:
2014-07-22
Description:
'Gain' of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers and is associated with poor prognosis. The well-characterized myelocytomatosis (MYC) oncogene resides in the 8q24.21 region and is consistently co-gained with an adjacent 'gene desert' of approximately 2 megabases that contains the long non-coding RNA gene PVT1, the CCDC26 gene candidate and the GSDMC gene. Whether low copy-number gain of one or more of these genes drives neoplasia is not known. Here we use chromosome engineering in mice to show that a single extra copy of either the Myc gene or the region encompassing Pvt1, Ccdc26 and Gsdmc fails to advance cancer measurably, whereas a single supernumerary segment encompassing all four genes successfully promotes cancer. Gain of PVT1 long non-coding RNA expression was required for high MYC protein levels in 8q24-amplified human cancer cells. PVT1 RNA and MYC protein expression correlated in primary human tumours, and copy number of PVT1 was co-increased in more than 98% of MYC-copy-increase cancers. Ablation of PVT1 from MYC-driven colon cancer line HCT116 diminished its tumorigenic potency. As MYC protein has been refractory to small-molecule inhibition, the dependence of high MYC protein levels on PVT1 long non-coding RNA provides a much needed therapeutic target.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767149/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767149/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Tseng, Yuen-Yi -- Moriarity, Branden S -- Gong, Wuming -- Akiyama, Ryutaro -- Tiwari, Ashutosh -- Kawakami, Hiroko -- Ronning, Peter -- Reuland, Brian -- Guenther, Kacey -- Beadnell, Thomas C -- Essig, Jaclyn -- Otto, George M -- O'Sullivan, M Gerard -- Largaespada, David A -- Schwertfeger, Kathryn L -- Marahrens, York -- Kawakami, Yasuhiko -- Bagchi, Anindya -- P30 CA077598/CA/NCI NIH HHS/ -- England -- Nature. 2014 Aug 7;512(7512):82-6. doi: 10.1038/nature13311. Epub 2014 Jun 22.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Center for Bio-Design, Translational Health Science and Technology Institute, Gurgaon 122016, India. ; Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA. ; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2]. ; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043044" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Cell Transformation, Neoplastic
;
Chromosomes, Human, Pair 8/genetics
;
DNA Copy Number Variations/*genetics
;
Disease Models, Animal
;
Gene Amplification/*genetics
;
Gene Dosage/*genetics
;
Genes, myc/*genetics
;
HCT116 Cells
;
Humans
;
Mice
;
Mice, Inbred C57BL
;
Oncogene Protein p55(v-myc)/*genetics/metabolism
;
Phenotype
;
RNA, Long Noncoding/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
