The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation.
Estrogen receptor α (ERα) is initially expressed in the majority of breast cancers and promotes estrogen-dependent cancer progression by regulating the transcription of genes linked to cell proliferation. ERα status is of clinical importance, as ERα-positive breast cancers can be successfully treated by adjuvant therapy with antiestrogens or aromatase inhibitors. Complications arise from the frequent development of drug resistance that might be caused by multiple alterations, including components of ERα signaling, during tumor progression and metastasis. Therefore, insights into the molecular mechanisms that control ERα expression and stability are of utmost importance to improve breast cancer diagnostics and therapeutics. Here we report that the atypical E3 ubiquitin ligase RNF31 stabilizes ERα and facilitates ERα-stimulated proliferation in breast cancer cell lines. We show that depletion of RNF31 decreases the number of cells in the S phase and reduces the levels of ERα and its downstream target genes, including cyclin D1 and c-myc. Analysis of data from clinical samples confirms correlation between RNF31 expression and the expression of ERα target genes. Immunoprecipitation indicates that RNF31 associates with ERα and increases its stability and mono-ubiquitination, dependent on the ubiquitin ligase activity of RNF31. Our data suggest that association of RNF31 and ERα occurs mainly in the cytosol, consistent with the lack of RNF31 recruitment to ERα-occupied promoters. In conclusion, our study establishes a non-genomic mechanism by which RNF31 via stabilizing ERα levels controls the transcription of estrogen-dependent genes linked to breast cancer cell proliferation.
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
J
J
Zhu
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
C
C
Zhao
1] Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden [2] Cancer Research Center, Cancer institute of Iran, Tehran University of Medical Sciences, Tehran, Iran.
A
A
Razavirad
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
T
T
Zhuang
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
P
P
Jonsson
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
N
N
Liang
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
C
C
Williams
Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
C-Y
CY
Lin
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
Y
Y
Qiao
Cancer Research Center, Cancer institute of Iran, Tehran University of Medical Sciences, Tehran, Iran.
K
K
Zendehdel
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
S
S
Strömblad
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
E
E
Treuter
Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
K
K
Dahlman-Wright
D001943:Breast Neoplasms; D049109:Cell Proliferation; D003600:Cytosol / Q000201:enzymology; D004958:Estradiol / Q000502:physiology; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D004967:Estrogens / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D021381:Protein Transport; D015398:Signal Transduction; D059467:Transcriptome; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry / Q000502:physiology*; D054875:Ubiquitination
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004958:Estradiol; C558338:RNF31 protein, human; D044767:Ubiquitin-Protein Ligases