A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer
Open Access
- 17 July 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 11 (1), 1-14
- https://doi.org/10.1038/s41467-020-17325-y
Abstract
Genetic variation at the 8q24 locus is linked with the greater susceptibility to prostate cancer in men of African ancestry. One such African ancestry specific rare variant, rs72725854 (A>G/T) (~6% allele frequency) has been associated with a ~2-fold increase in prostate cancer risk. However, the functional relevance of this variant is unknown. Here we show that the variant rs72725854 is present in a prostate cancer-specific enhancer at 8q24 locus. Chromatin-conformation capture and dCas9 mediated enhancer blocking establish a direct regulatory link between this enhancer and lncRNAs PCAT1, PRNCR1 and PVT1. The risk allele (‘T’) is associated with higher expression of PCAT1, PVT1 and c-myc in prostate tumors. Further, enhancer with the risk allele gains response to androgen stimulation by recruiting the transcription factor SPDEF whereas, non-risk alleles remain non-responsive. Elevated expression of these lncRNAs and c-myc in risk allele carriers may explain their greater susceptibility to prostate cancer.Funding Information
- U.S. Department of Defense (DOD PC180367)
- DST | Science and Engineering Research Board (SB/S2/RJN-071/2018)
- DBT India Alliance (IA/1/14/2/501539)
- Department of Atomic Energy, Government of India (12-R&D-TFR-5.04-0800)
- TIFR | National Centre for Biological Sciences (12-R&D-TFR-5.04-0900)
This publication has 53 references indexed in Scilit:
- Functional roles of enhancer RNAs for oestrogen-dependent transcriptional activationNature, 2013
- Exploring the effects of polymorphisms on cis-regulatory signal transduction responseTrends in Molecular Medicine, 2013
- An integrated encyclopedia of DNA elements in the human genomeNature, 2012
- Genome-wide analysis of ETS-family DNA-binding in vitro and in vivoThe EMBO Journal, 2010
- Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell IdentitiesMolecular Cell, 2010
- Assigning roles to DNA regulatory motifs using comparative genomicsBioinformatics, 2010
- A common genetic risk factor for colorectal and prostate cancerNature Genetics, 2007
- The PVT‐1 oncogene is a Myc protein target that is overexpressed in transformed cellsJournal of Cellular Physiology, 2007
- Multiple regions within 8q24 independently affect risk for prostate cancerNature Genetics, 2007
- Admixture mapping identifies 8q24 as a prostate cancer risk locus in African-American menProceedings of the National Academy of Sciences of the United States of America, 2006