MAD2L2 inhibits colorectal cancer growth by promoting NCOA3 ubiquitination and degradation.

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 (IP) coupled with mass spectrometry (IP-MS) 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 cells and mouse model in vitro and in vivo. The clinical significance of NCOA3 and its interaction partner protein in CRC patients was also studied. We identified mitotic arrest deficient 2-like protein 2 (MAD2L2, also known as MAD2B or REV7), with two signal peptide sequences of LIPLK and EVYPVGIFQK, to be an interaction partner of NCOA3. Overexpression of MAD2L2 suppressed the proliferation, migration, and clonogenicity of CRC cells by inducing the degradation of NCOA3. The mechanism study showed 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 found that MAD2L2 predicted favorable prognosis in CRC patients. We have discovered a novel role of MAD2L2 in the regulation of NCOA3 degradation and proposed that MAD2L2 serves as a tumor suppressor in CRC.

• Authors: Yixin Li, Liren Li, Miao Chen, Xinfa Yu, Zhuoyu Gu, Huijuan Qiu, Ge Qin, Qian Long, Xiaoyan Fu, Tianze Liu, Wenbin Li, Wenlin Huang, Dingbo Shi, Tiebang Kang, Meihua Luo, Xiaojun Wu, Wuguo Deng
• Journal: Molecular oncology (Mol Oncol) Vol. 12 Issue 3 Pg. 391-405 (03 2018) ISSN: 1878-0261 [Electronic] United States
• PMID: 29360267 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• MAD2L2 protein, human
• Mad2 Proteins
• NCOA3 protein, human
• Nuclear Receptor Coactivator 3

Topics

• Animals
• Cell Line, Tumor
• Colorectal Neoplasms (metabolism, pathology)
• Female
• HT29 Cells
• Humans
• Mad2 Proteins (genetics, metabolism)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Neoplasms, Experimental (metabolism, pathology)
• Nuclear Receptor Coactivator 3 (genetics, metabolism)
• Prognosis
• Proteolysis
• Ubiquitination
• Xenograft Model Antitumor Assays