Abstract B58: The role of epigenetic reader and alternative mRNA splicing variant MBD2_v2 in IL6 signaling in prostate cancer

Abstract

Background: African American men (AAM) have a 60% higher risk of being diagnosed with prostate cancer and a 2 to 3 times greater risk of dying from the disease compared to European American men (EAM). We previously reported evidence of molecular underpinnings for these disparities from high-throughput gene expression analysis of prostate cancer (PCa) specimens. The data showed that proinflammatory cytokine signaling factors, including IL6 and TGFB1, are significantly over-represented in PCa specimens from AAM. The limitation of that study, however, is that it did not investigate the potential molecular diversity for high-grade PCa, and it did not consider adjacent noncancer tissue. Methods: We conducted a pilot RNA-sequencing study of high-grade PCa, GS greater or equal to 7(4+3), and matched non-cancer adjacent prostate tissue specimens from AAM and EAM. We also studied the molecular biology of PCa cell lines derived from AAM and EAM tumors. Results: According to our genomic analysis, IL6 was once again relevant to our research, this time upregulated in PCa specimens from EAM, but also higher in the stromal compartment in AAM. Also, we noted that whether or not a PCa cell line expresses IL6 appears to be linked to TP53 mutation status. Moreover, cell lines derived from AAM (MDA-PCa-2b and RC77T), which are TP53 wild-type, did not express IL6 and showed an increased stem cell-like phenotype in response to IL6 treatment that was dose dependent. PCa cell lines that are TP53 mutant and expressed IL6 did not respond to exogenous IL6 treatment. We uncovered that in responsive PCa cell lines, IL6 treatment induced mRNA and protein expression of the epigenetic reader methyl CpG binding domain protein 2 (MBD2), more specifically the alternative mRNA splicing variant MBD2_v2. Further investigation validated that this short isoform promotes self-renewal and expansion of PCa stem cell-like cells. Conclusion: The outcomes suggest that there may be a dual nature for IL6 signaling in PCa that remains to be understood, yet contributes to the molecular diversity of high-grade prostate cancer and race disparities. Citation Format: Emily Girsch, Bin Bao, Cristina Mitrea, Wael A. Sakr, Gregory Dyson, Isaac Powell, Aliccia Bollig-Fischer. The role of epigenetic reader and alternative mRNA splicing variant MBD2_v2 in IL6 signaling in prostate cancer [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr B58.