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PVT1 dependence in cancer with MYC copy-number increase.
- Source :
-
Nature [Nature] 2014 Aug 07; Vol. 512 (7512), pp. 82-6. Date of Electronic Publication: 2014 Jun 22. - Publication Year :
- 2014
-
Abstract
- '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.
- Subjects :
- Animals
Cell Transformation, Neoplastic
Chromosomes, Human, Pair 8 genetics
Disease Models, Animal
HCT116 Cells
Humans
Mice
Mice, Inbred C57BL
Oncogene Protein p55(v-myc) metabolism
Phenotype
DNA Copy Number Variations genetics
Gene Amplification genetics
Gene Dosage genetics
Genes, myc genetics
Oncogene Protein p55(v-myc) genetics
RNA, Long Noncoding genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-4687
- Volume :
- 512
- Issue :
- 7512
- Database :
- MEDLINE
- Journal :
- Nature
- Publication Type :
- Academic Journal
- Accession number :
- 25043044
- Full Text :
- https://doi.org/10.1038/nature13311