Promoter of lncRNA Gene PVT1 Is a Tumor-Suppressor DNA Boundary Element.
Authors | |
Keywords | |
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. |
Year of Publication | 2018
|
Journal | Cell
|
Volume | 173
|
Issue | 6
|
Pages | 1398-1412.e22
|
Date Published | 2018 05 31
|
ISSN | 1097-4172
|
DOI | 10.1016/j.cell.2018.03.068
|
PubMed ID | 29731168
|
PubMed Central ID | PMC5984165
|
Links | |
Grant list | R21 NS101395 / NS / NINDS NIH HHS / United States
U01 CA168370 / CA / NCI NIH HHS / United States
T32 GM007618 / GM / NIGMS NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States
R01 DA036858 / DA / NIDA NIH HHS / United States
P50 HG007735 / HG / NHGRI NIH HHS / United States
T32 HG000044 / HG / NHGRI NIH HHS / United States
R35 CA209919 / CA / NCI NIH HHS / United States
R01 NS091544 / NS / NINDS NIH HHS / United States
S10 OD018220 / OD / NIH HHS / United States
|