NEDDylation negatively regulates ERRβ expression to promote breast cancer tumorigenesis and progression

Estrogen-related receptor beta (ERR beta) is downregulated in breast cancer cells and its overexpression in breast cancer patients is positively correlated with an improved prognosis and prolonged relapse-free survival. Here, we unravelled a molecular mechanism for ERR beta downregulation in breast cancer. We found that ERR beta is a key substrate of the SCF complex and that NEDDylation can activate the Cullin subunits of the SCF complex to target ERR beta for degradation in breast cancer. Consistently, using in vitro and in vivo models, we demonstrated that MLN4924, a specific small molecule inhibitor of NEDDylation, can restore ERR beta expression and culminate in a reduction in cell proliferation and migration of breast cancer cells. We also showed that increased ERR beta expression promotes the upregulation of its target genes, including the tumour suppressors p21(Cip1/Waf1)and E-cadherin, involved in cell proliferation and migration arrest at the gene promoter level. Interestingly, this tumour suppressive role of ERR beta does not depend on the expression of ER alpha in breast cancer. Moreover, our data revealed that the ERR beta recruits the transcription co-activator p300 to its targeted gene promoters to upregulate their expression. Collectively, our work revealed that restoration of ERR beta expression using the NEDDylation inhibitor MLN4924 can be a novel and effective strategy for breast cancer treatment.