Abstract B22: Molecular oncogenesis of NANOG in castration-resistant prostate cancer

Abstract

Abstract Regardless of the cell-of-origin, self-renewing tumor cells may be a driving force in cancer progression to lethal disease. An important outstanding question in the field of oncology is by what molecular mechanisms do tumor cells acquire stem cell (SC) biological properties? The embryonic stem cell pluripotency molecule NANOG appears to be among the important SC-related self-renewal genes underlying molecular oncogenesis. We have previously reported that NANOG attenuation inhibited prostate cancer cell clonogenic growth and in vivo tumorigenicity. Subsequently, we have found that NANOG overexpression in LNCaP prostate cancer cells promoted clonogenicity and tumor development particularly in androgen-deprived conditions. Furthermore, NANOG knockdown in relatively undifferentiated PSA- prostate cancer cells significantly reduced tumor regeneration in castrated hosts implicating NANOG in the emergence of castration-resistant prostate cancer (CRPC). To understand the molecular underpinnings of NANOG-mediated CRPC, we have performed ChIP-Seq analysis of NANOG occupancy in LNCaP cells overexpressing NANOGP8 or NANOG1. These non-biased and global studies have revealed downstream genes and signaling pathways that may potentially be regulated by NANOG in cancer cells and shed light on the NANOG castration-resistance phenotype. ∼60% of the promoter occupied sites are shared between NANOGP8 and NANOG1, representing 806 genes. Among these are many developmental-associated genes, chromatin remodeling and epigenetic regulators and molecules implicated in prostate cancer. In addition, motif analysis of NANOG occupied regions has revealed a novel candidate NANOG-interacting protein in prostate cancer cells. Integration of ChIP-Seq data with RNA-Seq is currently underway and integrative analysis is anticipated to further discriminate the direct and indirect molecular architecture responding to NANOG expression in prostate cancer. Citation Format: Collene R. Jeter, Yue Lu, Bigang Liu, Sally Gaddis, Shoudan Liang, Dean G. Tang. Molecular oncogenesis of NANOG in castration-resistant prostate cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B22.