2. Academic Validation
  3. ANXA10 promotes melanoma metastasis by suppressing E3 ligase TRIM41-directed PKD1 degradation

ANXA10 promotes melanoma metastasis by suppressing E3 ligase TRIM41-directed PKD1 degradation

  • Cancer Lett. 2021 Oct 28:519:237-249. doi: 10.1016/j.canlet.2021.07.033.
Xuerui Zhang 1,  Zhaoqing Hu 2,  Xinran Wang 2,  Lin Li 2,  Banghui Zhu 2,  Xiaolei Lin 2,  Jing Zhang 3,  Zichun Hua 4
Affiliations

Affiliations

  • 1 The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China; Changzhou High-Tech Research Institute of Nanjing University and Jiangsu Target Pharma Laboratories Inc., Changzhou, China.
  • 2 The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
  • 3 The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China. Electronic address: [email protected].
  • 4 The State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China; Changzhou High-Tech Research Institute of Nanjing University and Jiangsu Target Pharma Laboratories Inc., Changzhou, China; School of Biopharmacy, China Pharmaceutical University, Nanjing, China. Electronic address: [email protected].
PMID: 34324862 DOI: 10.1016/j.canlet.2021.07.033
Abstract

Melanoma is a highly metastatic Cancer that requires effective and targeted curative therapy. Annexin A10 (ANXA10), a member of the annexin family, is a calcium- and phospholipid-binding protein. Considerable evidence indicates that ANXA10 is involved in tumour progression, but little is known about its role in melanoma development. In this study, we find that ANXA10 expression is significantly upregulated, and correlates with melanoma progression. ANXA10 knockout profoundly reduces cell migration and the metastatic activity of melanoma. In addition, ANXA10 knockout induces the N- to E-cadherin switch by upregulating SMAD6, an inhibitory SMAD in the TGF-β/SMAD pathway. The negative regulation of SMAD6 by ANXA10 is dependent on PKD1. ANXA10 interacts with PKD1 and inhibits E3 Ligase TRIM41-targeted PKD1 degradation. In B16F10 melanoma cells, protein levels of ANXA10 and PKD1 are inversely correlated with SMAD6 level, but correlated with cell migration. Interestingly, ANXA10 and SMAD6 levels are inversely correlated in clinical samples of melanoma progression. Our findings suggest that the ANXA10-PKD1-SMAD6 axis is a new target for therapeutic strategies against melanoma metastasis.

Keywords

ANXA10; Cadherin switch; Melanoma metastasis; PKD1; SMAD6.

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