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 alpha (ERR alpha) 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 ERR alpha in breast cancer. Here, we investigated the interaction between FBXL10 and ERR alpha, and their protein expression and correlation in breast cancer. Mechanical studies revealed that FBXL10 stabilized ERR alpha protein levels by reducing its polyubiquitylation and promoting its mono-ubiquitylation. The reporter gene assay and examination of ERR alpha target genes validated the increased transcriptional activity of ERR alpha due to its increased protein levels by FBXL10. FBXL10 also increased ERR alpha enrichment at the promoter region of its target genes. Functionally, FBXL10 facilitated the ERR alpha/peroxisome proliferator-activated receptor gamma coactivator 1 beta (pGC1 beta)-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 ERR alpha to functional interaction with FBXL10. Moreover, a novel regulatory axis of FBXL10 and ERR alpha regulating the proliferation and tumorigenesis of breast cancer cells was established.

Automated summary

The study identified the interaction between orphan nuclear receptor ERR alpha and FBXL10 in breast cancer, showing that FBXL10 stabilized ERR alpha protein levels by reducing polyubiquitylation and promoting mono-ubiquitylation, resulting in increased transcriptional activity and proliferation of breast cancer cells. This study revealed a novel molecular mechanism underlying the regulation of ERR alpha and FBXL10 in breast cancer tumorigenesis.