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.

Rectal cancer sub-clones respond differentially to neoadjuvant therapy

“…Over-expression of DDX39 , an RNA helicase, was recently shown to promote cell migration, invasion, growth, and metastasis in hepatocellular carcinoma [27]. MAD2L2 is a spindle assembly checkpoint protein shown to inhibit colorectal cancer growth and is furthermore a favorable prognostic in colorectal patients demonstrating a strong potential resistance mechanism in this patient cohort [28].…”

Pan-cancer driver copy number alterations identified by joint expression/CNA data analysis

“… 66 AURKAIP1, FAAP20 67 , 68 MIIP MIIP, KIAA2013, SRM, PEX14, MAD2L2 1p36.22 Neither Neuroblastoma, breast cancer, etc. 66 MIIP, MAD2L2 69 , 70 CASP8AP2 CASP8AP2, SYNCRIP, MAP3K7, ZNF292, RNGTT 6q14.3 Ref. 18 CASP8AP2, MAP3K7 71 CCAR2 CCAR2, CHMP7, ELP3, CCDC25, INTS9 8p21.3 Ref.…”

“…The deletion of gene MIIP can induce chromosomal instability 69 . Tumor suppressor gene MAD2L2 inhibits cancer growth 70 . GSEA was applied to the genes of the two signatures UBE2J2 and signature MIIP, concluding that these genes are enriched in the GO term 'Negative Regulation of Cellular Component Organization' (P < 10 −4 , Q < 0.05), suggesting potential mechanisms associated with the evolutionary advantage of their simultaneous deletion.…”

ZNF350 promoter methylation accelerates colon cancer cell migration

“…A DNA methylation inhibitor attenuated migration ability through induction of IGFBP7 in colon cancer cell lines [39], and IGFBP7 could inhibit cell growth of breast tumor cells [40]. MAD2L2 interacted with NCOA3 and suppressed proliferation and migration of colon cancer cells [41]. SLIT3 was also induced by a DNA methylation inhibitor [42], and silencing of SLIT3 promoted proliferation, migration, and invasion with enhanced expression of MMP2 and MMP9 in lung cancer cells [43].…”