The PVT1 lncRNA is a novel epigenetic enhancer of MYC, and a promising risk-stratification biomarker in colorectal cancer

Molecular Cancer

Shusuke Toden¹  Kunitoshi Shigeyasu²  Ajay Goel³  Takatoshi Matsuyama⁴  Tsuyoshi Ozawa⁵  Takeshi Nagasaka⁶  Toshiyoshi Fujiwara⁶  Hiroyuki Uetake⁷  Toshiaki Ishikawa⁷  Pradipta Ghosh⁸  Debashis Sahoo⁹ 

[1] Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA;Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA;Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA;Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope Comprehensive Cancer Center, 1218 S. Fifth Avenue, Suite 2226, Duarte, CA, USA;Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA;Department of Specialized Surgery, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan;Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Charles A Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA;Department of Surgical Oncology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;Department of Specialized Surgery, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan;Departments of Medicine and Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA, USA;Departments of Pediatrics and Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA;

关键词: PVT1;    MYC;    Enhancer;    Epigenetic;    Prognostic marker;    Colorectal cancer;   

DOI  :  10.1186/s12943-020-01277-4

来源: Springer

【 摘 要 】

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 TGFβ/SMAD and Wnt/β-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.

【 授权许可】

CC BY