ANXA10 Promotes Melanoma Metastasis by Suppressing the Ubiquitination of PKD1 Mediated by E3 Ligase TRIM41

ABSTRACT: Melanoma is a highly metastatic type of cancer which requires novel and effective targeted therapies. Annexin A10 (ANXA10), a member of annexin family, is a calcium and phospholipid binding protein. Considerable evidences indicate that ANXA10 is involved in tumor progression, but little is known about the involvement of ANXA10 in melanoma. In this study, we reported that ANXA10 expression was significantly up-regulated and correlated with melanoma progression. Knockout of ANXA10 profoundly reduced cell migration and metastatic activity of melanoma. Mechanistic investigations showed that ANXA10 knockout induced N- to E-cadherin switch by upregulating SMAD6, an inhibitory SMAD in TGF-β/ SMAD pathway. The negative regulation of ANXA10 on SMAD6 was dependent on PKD1. We demonstrated that ANXA10 interacted with PKD1 and inhibited E3 ligase TRIM41-mediated PKD1 degradation. In B16F10 melanoma cells, the protein levels of ANXA10 and PKD1 were negatively correlated with SMAD6, but positively related to cell migration. In addition, a negative correlation of ANXA10 and SMAD6 levels was also observed in clinical samples, which was associated with melanoma progression. Our findings suggest that ANXA10/PKD1/ SMAD6 axis might be new targets of therapeutic strategies for melanoma metastasis.

ORGANISM(S): Mus musculus

PROVIDER: GSE174724 | GEO | 2021/05/20

REPOSITORIES: GEO