Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element

• Published in: Cell Vol. 173; no. 6; pp. 1398 - 1412.e22
• Main Authors: Cho, Seung Woo, Xu, Jin, Sun, Ruping, Mumbach, Maxwell R., Carter, Ava C., Chen, Y. Grace, Yost, Kathryn E., Kim, Jeewon, He, Jing, Nevins, Stephanie A., Chin, Suet-Feung, Caldas, Carlos, Liu, S. John, Horlbeck, Max A., Lim, Daniel A., Weissman, Jonathan S., Curtis, Christina, Chang, Howard Y.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 31.05.2018
• Subjects: Animals; breast neoplasms; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Carcinogenesis - genetics; cell growth; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Neoplastic; Chromatin; CRISPR-Cas Systems; CRISPRi; DNA; DNA, Neoplasm - genetics; enhancer; Enhancer Elements, Genetic; Female; gene editing; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genes, myc; Humans; lncRNA; loci; Mice; Mice, Inbred NOD; Mutation; MYC; neoplasm cells; Neoplasm Transplantation; oncogenes; promoter; Promoter Regions, Genetic; PVT1; regulatory sequences; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; topological domains; transcription (genetics); Transcription, Genetic; transcriptional regulation; tumor suppressor; enhancer; lncRNA; CRISPRi; PVT1; MYC; transcriptional regulation; tumor suppressor; promoter; topological domains
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2018.03.068

Noncoding mutations in cancer genomes are frequent but challenging to interpret. PVT1 encodes an oncogenic lncRNA, but recurrent translocations and deletions in human cancers suggest alternative mechanisms. Here, we show that the PVT1 promoter has a tumor-suppressor function that is independent of PVT1 lncRNA. CRISPR interference of PVT1 promoter enhances breast cancer cell competition and growth in vivo. The promoters of the PVT1 and the MYC oncogenes, located 55 kb apart on chromosome 8q24, compete for engagement with four intragenic enhancers in the PVT1 locus, thereby allowing the PVT1 promoter to regulate pause release of MYC transcription. PVT1 undergoes developmentally regulated monoallelic expression, and the PVT1 promoter inhibits MYC expression only from the same chromosome via promoter competition. Cancer genome sequencing identifies recurrent mutations encompassing the human PVT1 promoter, and genome editing verified that PVT1 promoter mutation promotes cancer cell growth. These results highlight regulatory sequences of lncRNA genes as potential disease-associated DNA elements. [Display omitted] •Silencing PVT1 promoter enhances breast cancer cell competition•PVT1 promoter inhibits MYC transcription independent of PVT1 lncRNA•PVT1 and MYC promoters compete for enhancer contact in cis•Mutations encompassing PVT1 promoter are recurrent in human cancers Recurrent mutations in human cancer are found encompassing the promotor for the lncRNA gene PVT1, which regulates MYC transcription via promoter competition for a shared set of enhancers.