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NEDDylation negatively regulates ERRβ expression to promote breast cancer tumorigenesis and progression
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NEDDylation negatively regulates ERRβ expression to promote breast cancer tumorigenesis and progression
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Journal Article
NEDDylation negatively regulates ERRβ expression to promote breast cancer tumorigenesis and progression
2020
Overview
Estrogen-related receptor beta (ERRβ) 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 ERRβ downregulation in breast cancer. We found that ERRβ is a key substrate of the SCF complex and that NEDDylation can activate the Cullin subunits of the SCF complex to target ERRβ 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 ERRβ expression and culminate in a reduction in cell proliferation and migration of breast cancer cells. We also showed that increased ERRβ 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 ERRβ does not depend on the expression of ERα in breast cancer. Moreover, our data revealed that the ERRβ recruits the transcription co-activator p300 to its targeted gene promoters to upregulate their expression. Collectively, our work revealed that restoration of ERRβ expression using the NEDDylation inhibitor MLN4924 can be a novel and effective strategy for breast cancer treatment.
Publisher
Nature Publishing Group UK,Springer Nature B.V
Subject
/ 13/95
/ 38
/ 38/1
/ 38/77
/ 38/89
/ 96
/ 96/1
/ 96/106
/ 96/109
/ Biomedical and Life Sciences
/ Breast Neoplasms - metabolism
/ Cell Proliferation - genetics
/ Cullin
/ Cullin Proteins - metabolism
/ Cyclin-dependent kinase inhibitor p21
/ Cyclopentanes - pharmacology
/ Estrogen Receptor alpha - metabolism
/ Estrogen Receptor beta - genetics
/ Estrogen Receptor beta - metabolism
/ Female
/ Gene Expression Regulation, Neoplastic - genetics
/ Humans
/ NEDD8 Protein - antagonists & inhibitors
/ Neoplasm Recurrence, Local - genetics
/ Receptors, Estrogen - metabolism
/ Tumors
