Abstract 5438: XPNPEP3: A novel transcriptional target of canonical Wnt/β-catenin signalling

Canonical Wnt/β-catenin signalling plays pivotal roles during embryonic development and adult tissue regeneration. Its aberrant activation however drives expression of a panoply of genes to facilitate colorectal tumorigenesis. Hence, it is imperative to delineate the complete β-catenin transcriptome. We performed genome-wide mRNA profiling of sporadic rectal cancer samples stratified by Wnt status. Results revealed significant up-regulation of XPNPEP3 transcript levels along with that of canonical Wnt targets AXIN2 and EPHB2 in Wnt+ samples. The differential expression of XPNPEP3 was further validated by quantitative PCR (Q-PCR) in additional samples. Nuclear stabilization of β-catenin achieved through LiCl treatment in three colorectal cancer (CRC) cell lines followed by Q-PCR and promoter-luciferase assays confirmed up-regulation of XPNPEP3. XPNPEP3 encodes X-prolyl aminopeptidase 3 which functions to remove the penultimate N-terminal Proline residue from nascent proteins and appears to play a role in ciliary function. Immunohistochemistry based expression analysis using a CRC tissue microarray revealed significant correlation between XPNPEP3 levels and β-catenin nuclear localization as well as increased XPNPEP3 expression in tumor compared to matched normal samples. Survival analysis of The Cancer Genome Atlas (TCGA) breast invasive carcinoma, skin cutaneous melanoma and lung adenocarcinoma data sets revealed poor survival among patients having perturbed XPNPEP3 expression. Characterization of possible oncogenic function of XPNPEP3 in CRC cells and in mice tumor xenografts is currently underway. Altogether, our results suggest XPNPEP3 to be a novel transcriptional target of Wnt/β-catenin signalling having a possible significance in CRC tumorigenesis. Citation Format: Raju Kumar, Ashmala Naz, Viswakalyan Kotapalli, Swarnalata Gowrishankar, Satish Rao, Jonathan R. Pollack, Murali Dharan Bashyam. XPNPEP3: A novel transcriptional target of canonical Wnt/β-catenin signalling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5438.