FBXL10 promotes ERRα protein stability and proliferation of breast cancer cells by enhancing the mono-ubiquitylation of ERRα

The underlying mechanism of orphan nuclear receptor estrogen-related receptor α (ERRα) in breast cancer was investigated by identifying its interaction partners using mass spectrometry. F-box and leucine-rich repeat protein 10 (FBXL10), which modulates various physiological processes, may interact with ERRα in breast cancer. Here, we investigated the interaction between FBXL10 and ERRα, and their protein expression and correlation in breast cancer. Mechanical studies revealed that FBXL10 stabilized ERRα protein levels by reducing its poly-ubiquitylation and promoting its mono-ubiquitylation. The reporter gene assay and examination of ERRα target genes validated the increased transcriptional activity of ERRα due to its increased protein levels by FBXL10. FBXL10 also increased ERRα enrichment at the promoter region of its target genes. Functionally, FBXL10 facilitated the ERRα/peroxisome proliferator-activated receptor gamma coactivator 1 β (PGC1β)-mediated proliferation and tumorigenesis of breast cancer cells in vitro and in vivo . Our results uncovered a molecular mechanism linking the mono-ubiquitylation and protein stability of ERRα to functional interaction with FBXL10. Moreover, a novel regulatory axis of FBXL10 and ERRα regulating the proliferation and tumorigenesis of breast cancer cells was established. • FBXL10 and ERRα have high expression as well as positive correlation in breast cancer. • FBXL10 physically interests with ERRα and enhances the mono-ubiquitylation and stability of ERRα. • FBXL10 promotes the enrichment of ERRα at the promoters of its targeted genes and increases the transcription activity of ERRα. • FBXL10 facilitates the ERRα/PGC1β-mediated proliferation and tumorigenesis of breast cancer cells in vitro and in vivo.