Journal
MOLECULAR CANCER
Volume 19, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12943-020-01277-4
Keywords
PVT1; MYC; Enhancer; Epigenetic; Prognostic marker; Colorectal cancer
Categories
Funding
- National Institute of Health [CA72851, CA181572, CA184792, CA187956, CA202797, CA238042, UG3TR002968, GM138385]
- Uehara Memorial Foundation
- JSPS [20 K17653]
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Accumulating evidence suggests that dysregulation of transcriptional enhancers plays a significant role in cancer pathogenesis. Herein, we performed a genome-wide discovery of enhancer elements in colorectal cancer (CRC). We identified PVT1 locus as a previously unrecognized transcriptional regulator in CRC with a significantly high enhancer activity, which ultimately was responsible for regulating the expression of MYC oncogene. High expression of the PVT1 long-non-coding RNA (lncRNA) transcribed from the PVT1 locus was associated with poor survival among patients with stage II and III CRCs (p < 0.05). Aberrant methylation of the PVT1 locus inversely correlated with the reduced expression of the corresponding the PVT1 lncRNA, as well as MYC gene expression. Bioinformatic analyses of CRC-transcriptomes revealed that the PVT1 locus may also broadly impact the expression and function of other key genes within two key CRC-associated signaling pathways - the TGF beta/SMAD and Wnt/beta-Catenin pathways. We conclude that the PVT1 is a novel oncogenic enhancer of MYC and its activity is controlled through epigenetic regulation mediated through aberrant methylation in CRC. Our findings also suggest that the PVT1 lncRNA expression is a promising prognostic biomarker and a potential therapeutic target in CRC.
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