コンテンツへスキップ
Merck
  • NEDDylation negatively regulates ERRβ expression to promote breast cancer tumorigenesis and progression.

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

Cell death & disease (2020-08-26)
Sanoj K Naik, Eric W-F Lam, Monalisa Parija, Surya Prakash, Yannasittha Jiramongkol, Amit K Adhya, Dilip K Parida, Sandip K Mishra
要旨

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 p21Cip1/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.

材料
製品番号
ブランド
製品内容

Sigma-Aldrich
モノクロナール抗α-チューブリン マウス宿主抗体, clone DM1A, ascites fluid
Sigma-Aldrich
モノクロナール抗p300/CBP マウス宿主抗体, clone NM11, purified from hybridoma cell culture
Sigma-Aldrich
Anti-UBA3 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution