AAMP promotes colorectal cancer metastasis by suppressing SMURF2-mediated ubiquitination and degradation of RhoA

Abstract

Metastasis is considered the leading cause of cancer death due to the limited possibilities to therapeutically target this process. How the ubiquitination machinery contributes to metastasis remains underexplored. Angio-associated migratory cell protein (AAMP), a ubiquitously expressed protein involved in cell migration, has been reported to play oncogenic roles in breast and non-small cell lung cancer (NSCLC). However, the role of AAMP in colorectal cancer (CRC) has not been demonstrated. Here, we report that AAMP is aberrantly upregulated in metastatic CRC and that AAMP upregulation is correlated with the poor survival of CRC patients. AAMP knockdown significantly attenuated the migration and invasion of CRC cells, while AAMP overexpression led to the opposite effects. Mechanistically, we identified Ras homolog family member A (RhoA) as a target of AAMP. Smad ubiquitin regulatory factor (SMURF) 2 was previously found to be a CRC suppressor. Notably, we discovered here that SMURF2 acted as an E3 ubiquitin ligase to mediate the ubiquitination and degradation of RhoA. AAMP stabilized RhoA by binding to it and suppressing its SMURF2-mediated ubiquitination and degradation. Subsequently, the level of active RhoA was increased, thereby accelerating CRC cell migration and invasion. These findings indicate a new potential antitumor target for CRC.

B7-H3 Inhibitors in Oncology Clinical Trials: A Review

“…[ 68 ] AAMP has also been identified to promote colorectal cancer and NSCLC cell migration and invasion, further raising interest as a potential therapeutic target. [ 69 , 70 ] Because B7-H3 is also noted to play an important role in these cancer types, a combination approach targeting both B7-H3 and AAMP could be promising in NSCLC, CRC, and GBM.…”

Pan-cancer analysis from multi-omics data reveals AAMP as an unfavourable prognostic marker

“…Recent studies have shown that AAMP mainly locates in the cytoplasm and membrane of vascular endothelial cells, affecting the angiogenesis, diffusion, migration, and cytoskeleton remodeling processes of endothelial cells [ 25 , 26 ]. In addition, it has been reported that AAMP is abnormally up-regulated in metastatic CRC and boosts the occurrence of colorectal cancer by inhibiting SMURF2-mediated RhoA liquefaction and degradation [ 27 ]. Furthermore, AAMP is highly expressed in invasive gastrointestinal and breast carcinoma cells and is a marker of poor prognosis [ 4 , 28 ].…”

Role of Post-Translational Modifications in Colorectal Cancer Metastasis

“…FBX8 regulates the ubiquitination and stability of GSTP1, which inhibits the invasion and metastasis of CRC cells in vivo and in vitro [77]. SMURF2 acts as an E3 ubiquitin ligase to mediate the ubiquitination and degradation of RhoA, thereby decelerating the migration and invasion of CRC cells [79] (Figure 4).…”