A rare variant of African ancestry activates 8q24 lncRNA hub by modulating cancer associated enhancer

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.

Document Details

Document Type
Pub Defense Publication
Publication Date
Jul 17, 2020
Source ID
10.1038/s41467-020-17325-y

Entities

People

  • Anurag Kumar Singh
  • Ashwin Nair
  • Bharath Saravanan
  • Christopher A. Haiman
  • Deepanshu Soota
  • Dimple Notani
  • Kaivalya Walavalkar
  • Matthew L Freedman
  • Padubidri V Shivaprasad
  • Radhakrishnan Sabarinathan
  • Rajat Mann
  • Ranveer Singh Jayani
  • Umer Farooq
  • Zubairul Islam

Organizations

  • Department of Atomic Energy
  • National Centre for Biological Sciences
  • Science and Engineering Research Board
  • United States Department of Defense
  • Wellcome Trust/DBT India Alliance

Tags

Fields of Study

  • Biology

Readers

  • Molecular Biology and Genetics
  • Molecular Genetics
  • Prostate Cancer Biology.

Technology Areas

  • Biotechnology