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

Seung Woo Cho, Jin Xu, Ruping Sun, Maxwell R. Mumbach, Ava C. Carter, Y. Grace Chen, Kathryn E. Yost, Jeewon Kim, Jing He, Stephanie A. Nevins, Suet Feung Chin, Carlos Caldas, S. John Liu, Max A. Horlbeck, Daniel A. Lim, Jonathan S. Weissman, Christina Curtis, Howard Y. Chang

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)1398-1412.e22
JournalCell
Volume173
Issue number6
DOIs
StatePublished - May 31 2018
Externally publishedYes

Keywords

  • CRISPRi
  • MYC
  • PVT1
  • enhancer
  • lncRNA
  • promoter
  • topological domains
  • transcriptional regulation
  • tumor suppressor

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    Cho, S. W., Xu, J., Sun, R., Mumbach, M. R., Carter, A. C., Chen, Y. G., Yost, K. E., Kim, J., He, J., Nevins, S. A., Chin, S. F., Caldas, C., Liu, S. J., Horlbeck, M. A., Lim, D. A., Weissman, J. S., Curtis, C., & Chang, H. Y. (2018). Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element. Cell, 173(6), 1398-1412.e22. https://doi.org/10.1016/j.cell.2018.03.068