RNF12 is regulated by AKT phosphorylation and promotes TGF-β driven breast cancer metastasis.

Abstract

Transforming growth factor-β (TGF-β) acts as a pro-metastatic factor in advanced breast cancer. RNF12, an E3 ubiquitin ligase, stimulates TGF-β signaling by binding to the inhibitory SMAD7 and inducing its proteasomal degradation. How RNF12 activity is regulated and its exact role in cancer is incompletely understood. Here we report that RNF12 was overexpressed in invasive breast cancers and its high expression correlated with poor prognosis. RNF12 promoted breast cancer cell migration, invasion, and experimental metastasis in zebrafish and murine xenograft models. RNF12 levels were positively associated with the phosphorylated AKT/protein kinase B (PKB) levels, and both displayed significant higher levels in the basal-like subtype compared with the levels in luminal-like subtype of breast cancer cells. Mechanistically, AKT-mediated phosphorylation induced the nuclear localization of RNF12, maintained its stability, and accelerated the degradation of SMAD7 mediated by RNF12. Furthermore, we demonstrated that RNF12 and AKT cooperated functionally in breast cancer cell migration. Notably, RNF12 expression strongly correlated with both phosphorylated AKT and phosphorylated SMAD2 levels in breast cancer tissues. Thus, our results uncovered RNF12 as an important determinant in the crosstalk between the TGF-β and AKT signaling pathways during breast cancer progression.

• Authors: Yongsheng Huang, Sijia Liu, Mengjie Shan, Sophie C Hagenaars, Wilma E Mesker, Danielle Cohen, Lin Wang, Zhi Zheng, Peter Devilee, Rob A E M Tollenaar, Zhangfu Li, Yongmei Song, Long Zhang, Dan Li, Peter Ten Dijke
• Journal: Cell death & disease (Cell Death Dis) Vol. 13 Issue 1 Pg. 44 (01 10 2022) ISSN: 2041-4889 [Electronic] England
• PMID: 35013159 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022. The Author(s).

Chemical References

• Transforming Growth Factor beta
• RLIM protein, human
• Ubiquitin-Protein Ligases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Movement
• Cell Nucleus (metabolism)
• Female
• Humans
• Mice
• Neoplasm Invasiveness
• Neoplasm Metastasis
• Phosphorylation
• Prognosis
• Protein Stability
• Proto-Oncogene Proteins c-akt (metabolism)
• Signal Transduction
• Transforming Growth Factor beta (metabolism)
• Ubiquitin-Protein Ligases (genetics, metabolism)
• Zebrafish