Abstract 4016: Epigenetic regulation of CXCR3 splicing in prostate cancer cells

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 8_Supplement; p. 4016
• Main Authors: Kumar, Devi Sharanya Sampath, Wells, Alan
• Format: Journal Article
• Language: English
• Published: 15.04.2012
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-4016

Abstract Prostate cancer is the second leading cause of cancer death among men, with the metastasis of these tumors being the main reason for the high rates of mortality and morbidity. This tumor progression requires epithelial cell dedifferentiation, migration, invasion and growth in an ectopic site. CXCR3 is a G-protein coupled receptor whose splicing was found to be differentially regulated in prostate cancer. We have found over-expression of the CXCR3A splice isoform in prostate cancers and cell lines whereas normal prostate epithelium expresses by and large only the CXCR3B isoform, representing a possible switch in the expression between the CXCR3 splice variants. As these variants link differentially to pro- and anti-invasion signaling pathways, this may explain the relentless progression of the prostate carcinoma cells. The switch is present at both the RNA and the protein level which suggests that the altering factor is at the trancriptional control level. We hypothesized that a mutation in the gene or an epigenetic modification of the genome could possibly be regulating the splicing event and hence the switch in the expression. CXCR3 when scanned for mutations was found to be intact except for a polymorphism in the intronic region which coincided with the normal prostate cells. On the epigenetic regulation side, the CpG dinucleotides in the regulatory regions, the one intron and 5′ upstream region, susceptible to methylation changes were analysed for methylation differences. The upstream sequence does not show a differential methylation pattern whereas the intronic region shows differential methylation between the cancer and normal prostate cells at 3 different nucleotides. A possible explanation is that the methylation in the introns alters the speed of the transcription machinery allowing more time for a particular splice variant to be transcribed more than the other. A bichromatic reporter minigene has been designed for each of the differentially methylated CpG nucleotides, to study its effects on the splicing regulation of the CXCR3 gene. Further studies include expressing the minigene and documenting the splicing differences. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4016. doi:1538-7445.AM2012-4016