The atypical ubiquitin ligase RNF31 stabilizes estrogen receptor α and modulates estrogen-stimulated breast cancer cell proliferation

Abstract

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.

Ubiquitylation of nuclear receptors: new linkages and therapeutic implications

“…BRCA1 ubiquitylation of both ERα and PR contributes to the their transcriptional function (Eakin et al 2007; Calvo & Beato 2011). BRCA1/BARD1 monoubiquitylates ERα in vitro and in vivo (Eakin et al 2007; Dizin & Irminger-Finger 2010; Ma et al 2010; Zhu et al 2014). This monoubiquitylation is dependent on BRCA1/BARD1 ligase activity as cancer pre-disposing BRCA1 mutations (C61G and C64G) affecting the ligase activity abolish the ability of BRCA1 to monoubiquitylate ERα.…”

miR-503 suppresses tumor cell proliferation and metastasis by directly targeting RNF31 in prostate cancer

“…Proliferation and metastasis are two most common causes for the cancer-related death [14,34]. In order to identify the functions of RNF31, the stable RNF31 silence/overexpression PCa cell lines were constructed and the effects of them on cell proliferation, migration and invasion were studied.…”

“…This complex has the unique ability to catalyze the formation of linear peptide bonds between the amino-terminal methionine of one ubiquitin molecule and the carboxyl-terminal glycine of the adjacent ubiquitin [13]. RNF31 could constitute a valuable diagnostic tool and/or a drug target for ERa-positive breast cancers [14,15]. Inhibition of RNF31 activity can affect p53 signaling to enhance the effect of chemotherapy [14,15].…”

“…RNF31 could constitute a valuable diagnostic tool and/or a drug target for ERa-positive breast cancers [14,15]. Inhibition of RNF31 activity can affect p53 signaling to enhance the effect of chemotherapy [14,15]. It is well known that miRNAs are small non-coding RNA molecules consisting of 19e23 nucleotides that can regulate various biological processes.…”

Roles of microRNA-221/222 in type 2 diabetic patients with post-menopausal breast cancer

“…Estrogen exerts its regulation on cell proliferation by binding to the estrogen receptors on target cells (Zhu et al, 2014). The major estrogenic hormones are estradiol and estrone.…”