PVT1 dependence in cancer with MYC copy-number increase

By Yuen-Yi Tseng, Branden S. Moriarity, Wuming Gong, Ryutaro Akiyama, A. Tiwari, H. Kawakami, Peter Ronning, B. Reuland, K. Guenther, Thomas C. Beadnell and 8 more. Nature, 2014

681 citations recorded by the source corpus.

‘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.

Subfields: Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/56af99b50ad7e50233ada75d294e40fac45ec0ac

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Citations in the corpus

LncRNA-mediated regulation of cell signaling in cancer (2017, background): “Suppression of PVT1 inhibits c-Myc-driven tumorigenic potency (Tseng et al 2014).”
Noncoding RNA:RNA Regulatory Networks in Cancer (2018, background): “PVT1 is a well-known oncogenic lncRNA which is often co-amplified with the proto-oncogene MYC (MYC proto-oncogene, bHLH transcription factor) and is required for elevated MYC expression in cancer [101].”
Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. (2018, background): “Overall, our observations for PVT1 in M3-UM are consistent with it being highly regulated by DNA methylation in renal cell carcinoma (Posa et al., 2016), acting as an independent oncogene and enhancing MYC protein levels/activity (Tseng et al., 2014).”
How do lncRNAs regulate transcription? (2017, background): “A mutagenesis studyofCTCFandoneof its RNAbinders—MYCNOS lncRNA— implicated zinc fingers 9 to 11 (500 to 576 amino acids) of CTCF and exons1 and3ofMYCNOS lncRNAas the crucial interacting regions (137). a-Thalassemia/mental retardation X-linked a-Thalassemia/mental retardationX-linked (ATRX) is a tran”
MYC, Metabolism, and Cancer. (2015, background): “Recent studies show that long noncoding RNAs control MYC activity and protein stability by altering posttranslational modification (15, 21).”
Linking Long Noncoding RNA Localization and Function. (2016, background): “PVT1 interferes with phosphorylation of MYC at Thr58 in the nucleus, which subsequently increases MYC stability and leads to elevated MYC levels in cancers [26].”
Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy (2018, positive): “E-box sites; (5) T cell low tumors had elevated expression of Pvt1 (Figure 6D), a long non-coding RNA that facilitates high MYC levels (Tseng et al., 2014); and (6) previous reports support a role for MYC in promoting an immunosuppressive TME (Casey et al.”
CRISPRi-based genome-scale identification of functional long non-coding RNA loci in human cells (2016, neutral): “Because PVT1 had previously been characterized as a proto-oncogene (45) and pro-growth phenotypes in cancer cell lines are uncommon (23, 46), we validated the pro-growth phenotype (Fig.”
Colorectal Carcinoma: A General Overview and Future Perspectives in Colorectal Cancer (2017, background): “Increase of cell proliferation and cell-cycle progression [115,116]”