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

doi:10.1016/j.cell.2018.03.068

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

Cell. 2018 May 31;173(6):1398-1412.e22. doi: 10.1016/j.cell.2018.03.068. Epub 2018 May 3.

Authors

Seung Woo Cho¹, Jin Xu¹, Ruping Sun², Maxwell R Mumbach¹, Ava C Carter¹, Y Grace Chen¹, Kathryn E Yost¹, Jeewon Kim³, Jing He¹, Stephanie A Nevins¹, Suet-Feung Chin⁴, Carlos Caldas⁵, S John Liu⁶, Max A Horlbeck⁷, Daniel A Lim⁸, Jonathan S Weissman⁷, Christina Curtis², Howard Y Chang⁹

Affiliations

¹ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
² Departments of Medicine and Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford, CA 94305, USA.
³ Stanford Cancer Institute, Stanford, CA 94305, USA.
⁴ Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK.
⁵ Department of Oncology and Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge CB2 0RE, UK; Breast Cancer Program, CRUK Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 2QQ, UK.
⁶ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA.
⁷ Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA; Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA; California Institute for Quantitative Biomedical Research, University of California, San Francisco, San Francisco, CA 94143, USA.
⁸ Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143, USA; Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, San Francisco, CA 94143, USA; San Francisco Veterans Affairs Medical Center, San Francisco, San Francisco, CA 94121, USA.
⁹ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA. Electronic address: howchang@stanford.edu.

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.

Keywords: CRISPRi; MYC; PVT1; enhancer; lncRNA; promoter; topological domains; transcriptional regulation; tumor suppressor.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
CRISPR-Cas Systems
Carcinogenesis / genetics
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
Chromatin
DNA, Neoplasm / genetics
Enhancer Elements, Genetic
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic*
Genes, myc*
Humans
Mice
Mice, Inbred NOD
Mutation
Neoplasm Transplantation
Promoter Regions, Genetic
RNA, Long Noncoding / genetics*
RNA, Long Noncoding / metabolism
Transcription, Genetic

Substances

Chromatin
DNA, Neoplasm
PVT1 long-non-coding RNA, human
RNA, Long Noncoding

Abstract

Publication types

MeSH terms

Substances

Grants and funding