AAMP promotes colorectal cancermetastasis by suppressing SMURF2-mediatedubiquitination and degradation of RhoA

Yuhui Wu; Bofang Liu; Weiqiang Lin; Rongjie Zhao; Weidong Han; Jiansheng Xie

doi:10.1016/j.omto.2021.11.007

AAMP promotes colorectal cancermetastasis by suppressing SMURF2-mediatedubiquitination and degradation of RhoA

Mol Ther Oncolytics. 2021 Nov 11:23:515-530. doi: 10.1016/j.omto.2021.11.007. eCollection 2021 Dec 17.

Authors

Yuhui Wu¹, Bofang Liu¹, Weiqiang Lin², Rongjie Zhao¹, Weidong Han¹, Jiansheng Xie^{1

3}

Affiliations

¹ Department of Medical Oncology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China.
² Laboratory of Cancer Biology, Institute of Clinical Science, The Fourth Affiliated Hospital, College of Medicine, Zhejiang University, Yiwu, Zhejiang 322000, China.
³ Laboratory of Cancer Biology, Institute of Clinical Science, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310016, China.

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.

Keywords: AAMP; RhoA; SMURF2; colorectal cancer; metastasis; ubiquitination.