Abstract 3370: Mad2l2 inhibits colorectal cancer growth by promoting ncoa3 ubiquitination and degradation

Abstract

Abstract Nuclear receptor coactivator 3 (NCOA3) is a transcriptional coactivator that has elevated expression in multiple tumor types, including colorectal cancer (CRC). However, the molecular mechanisms that regulate the tumorigenic functions of NCOA3 in CRC remain largely unknown. In this study, we aimed to discover and identify the novel regulatory proteins of NCOA3 and explore their mechanisms of action. Immunoprecipitation coupled with mass spectrometry analysis was used to detect, identify and verify the proteins that interacted with NCOA3 in CRC cells. The biological functions of the candidate proteins and the underlying molecular mechanism were investigated in CRC cell lines and a mouse model in vitro and in vivo. The clinical significance of NCOA3 and its interaction partner protein in CRC patients was also studied. We discovered and identified mitotic arrest deficient 2-like protein 2 (MAD2L2, also known as MAD2B or REV7) as an interaction partner of NCOA3 by immunoprecipitation coupled with mass spectrometry analysis. Overexpression of MAD2L2 suppressed the cell proliferation, migration and clonogenecity in CRC cell lines and a mouse model by inducing the degradation of NCOA3. We also found that increased MAD2L2 expression in CRC cells activated p38, which was required for the phosphorylation of NCOA3 that led to its ubiquitination and degradation by the proteasome. Moreover, we demonstrated that MAD2L2 predicted favorable prognosis in CRC patients. These results indicate that MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation. Our study have discovered a novel role of MAD2L2 in the regulation of NCOA3 degradation, and proposed that MAD2L2 serves as a potential tumor suppressor in CRC. Citation Format: yixin li, ge qin, qian long, changlin zhang, dingbo shi, miao chen, wuguo deng. Mad2l2 inhibits colorectal cancer growth by promoting ncoa3 ubiquitination and degradation [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 3370.