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

• Published in: Cell death & disease 2022-01, Vol.13 (1), p.44-44, Article 44
• Main Authors: Huang, Yongsheng, Liu, Sijia, Shan, Mengjie, Hagenaars, Sophie C., Mesker, Wilma E., Cohen, Danielle, Wang, Lin, Zheng, Zhi, Devilee, Peter, Tollenaar, Rob A. E. M., Li, Zhangfu, Song, Yongmei, Zhang, Long, Li, Dan, ten Dijke, Peter
• Format: Article
• Language: English
• Subjects: 13; 13/1; 13/106; 13/109; 13/51; 13/95; 14; 14/32; 14/63; 38; 631/67; 631/80; AKT protein; Animal models; Animals; Antibodies; Biochemistry; Biomedical and Life Sciences; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell adhesion & migration; Cell Biology; Cell Culture; Cell Line, Tumor; Cell migration; Cell Movement; Cell Nucleus - metabolism; Female; Humans; Immunology; Invasiveness; Kinases; Life Sciences; Localization; Metastases; Metastasis; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Phosphorylation; Prognosis; Proteasomes; Protein Stability; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Smad2 protein; Smad7 protein; Transforming Growth Factor beta - metabolism; Transforming growth factor-b; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Xenografts; Zebrafish
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-021-04493-y

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.