Abstract 3673: BVES dependent regulation of YAP1 in colorectal cancer cells

Colorectal cancer (CRC) has a US incidence rate of almost 150,000 cases and accounts for over 10% of new cancer diagnoses. Dysfunction of epithelial adherens junctions and tight junctions (TJs) have long been implicated in CRC growth and metastasis The Popeye domain containing family of proteins are TJ-associated and appear to nucleate TJ formation. BVES or POPDC1 is one member of this family and is under-expressed in all stages of human colorectal carcinoma (CRC). On the other hand, YAP1 a novel oncogene in the Hippo pathway is up-regulated in many cancers including colon cancer. In the present study, we report an inverse correlation between tumor suppressor protein BVES and oncogene YAP1 in human colorectal carcinoma tumor samples and human colon cancer cell lines. We demonstrate that ectopic expression of BVES in BVES deficient cells decreases YAP1 protein while knocking down BVES in cells expressing BVES increases YAP1 levels. Cycloheximide (CHX) experiments indicate that this is likely occurring at the level of protein stability. CDK6 is a cell cycle regulator and YAP1 transcriptional target, and its levels are increased in the setting of BVES-knockdown in CACO2 cells. Concurrent with this there is increased cell growth. Conversely, when BVES is overexpressed, CDK6 transcription is reduced. Further knocking down of YAP1 in BVES knocked down cells reverses the cell growth advantage suggesting that BVES regulation of cell growth in part is dependent upon YAP1 protein levels. Co-immunoprecipitation (Co-IP) and yeast-2-hybrid (Y2H) assay also shows a direct interaction of BVES and YAP1. In sum, these findings suggest a novel mechanism underlying BVES tumor-suppressive function through regulation of a potential growth modulator, YAP1 in colorectal cancer. Citation Format: Mukul K. Mittal, Anthony Bilotta, Cody E. Keating, Sarah P. Short, Christopher S. Williams. BVES dependent regulation of YAP1 in colorectal cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3673.