Abstract
BACKGROUND: RING finger protein 135 (RNF135) is identified as a regulator in certain cancer types. However, its role and molecular mechanisms in breast cancer are still unclear. METHODS: Herein, we investigated the level of RNF135 in tumor tissues of breast patients using the online database and confirmed the data by real-time PCR and western blot analysis. The effects of RNF135 on stemness maintenance and migration/invasion capability of breast cells were investigated by sphere formation, flow cytometry, and transwell assays. Limiting dilution xenograft assay and metastatic model were applied to assess the implications of RNF135 in tumorigenesis, chemoresistance, and metastasis. RESULTS: Our results revealed that RNF135 was upregulated in tumor tissues of breast patients, especially in metastatic patients. Knockdown of RNF135 suppressed stemness, and migration/invasion capability of breast cancer cells. Conversely, RNF135 overexpression enhanced the stemness and migration/invasion ability of breast cancer cells. Limiting dilution xenograft and metastatic assays demonstrated that RNF135 was required for the self-renewal of CSCs to initiate breast cancer development and metastasis. Mechanistically, DDX58 was identified as the substrate of RNF135 and RNF135 could facilitated the ubiquitination and degradation of DDX58. Notably, overexpression of DDX58 rescued the promoting effects of RNF135 on the stemness and migration/invasion ability of breast cancer cells. CONCLUSIONS: Overall, our results implied that RNF135 promotes the stemness of breast cancer cells by ubiquitinating and degrading DDX58 and targeting of RNF135/DDX58 axis might be a feasible method to suppress tumorigenesis and metastasis of breast cancer patients.