A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer.
|Title||A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer.|
|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Walavalkar K, Saravanan B, Singh AKumar, Jayani RSingh, Nair A, Farooq U, Islam Z, Soota D, Mann R, Shivaprasad PV, Freedman ML, Sabarinathan R, Haiman CA, Notani D|
|Date Published||2020 Jul 17|
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.
|Alternate Journal||Nat Commun|
|PubMed Central ID||PMC7368061|
|Grant List||DOD PC180367 / / U.S. Department of Defense (United States Department of Defense) / |
SB/S2/RJN-071/2018 / / DST | Science and Engineering Research Board (SERB) /
IA/1/14/2/501539 / / DBT India Alliance (Wellcome Trust/DBT India Alliance) /
12-R&D-TFR-5.04-0800 / / Department of Atomic Energy, Government of India (DAE) /
12-R&D-TFR-5.04-0900 / / TIFR | National Centre for Biological Sciences (NCBS) /