Abstract
BackgroundE3 ubiquitin ligase HRD1 (HMG-CoA reductase degradation protein 1, alias synoviolin with SYVN1 as the official gene symbol) was found downregulated and acting as a tumor suppressor in breast cancer, while the exact expression profile of HRD1 in different breast cancer subtypes remains unknown. Recent studies characterized circular RNAs (circRNAs) playing an regulatory role as miRNA sponge in tumor progression, presenting a new viewpoint for the post-transcriptional regulation of cancer-related genes.MethodsExamination of the expression of HRD1 protein and mRNA was implemented using public microarray/RNA-sequencing datasets and breast cancer tissues/cell lines. Based on public RNA-sequencing results, online databases and enrichment/clustering analyses were used to predict the specific combinations of circRNA/miRNA that potentially govern HRD1 expression. Gain-of-function and rescue experiments in vitro and in vivo were executed to evaluate the suppressive effects of circNR3C2 on breast cancer progression through HRD1-mediated proteasomal degradation of Vimentin, which was identified using immunoblotting, immunoprecipitation, and in vitro ubiquitination assays.ResultsHRD1 is significantly underexpressed in triple-negative breast cancer (TNBC) against other subtypes and has an inverse correlation with Vimentin, inhibiting the proliferation, migration, invasion and EMT (epithelial-mesenchymal transition) process of breast cancer cells via inducing polyubiquitination-mediated proteasomal degradation of Vimentin. CircNR3C2 (hsa_circ_0071127) is also remarkably downregulated in TNBC, negatively correlated with the distant metastasis and lethality of invasive breast carcinoma. Overexpressing circNR3C2 in vitro and in vivo leads to a crucial enhancement of the tumor-suppressive effects of HRD1 through sponging miR-513a-3p.ConclusionsCollectively, we elucidated a bona fide circNR3C2/miR-513a-3p/HRD1/Vimentin axis that negatively regulates the metastasis of TNBC, suggesting that circNR3C2 and HRD1 can act as potential prognostic biomarkers. Our study may facilitate the development of therapeutic agents targeting circNR3C2 and HRD1 for patients with aggressive breast cancer.
Highlights
E3 ubiquitin ligase HRD1 (HMG-CoA reductase degradation protein 1, alias synoviolin with SYVN1 as the official gene symbol) was found downregulated and acting as a tumor suppressor in breast cancer, while the exact expression profile of HRD1 in different breast cancer subtypes remains unknown
HRD1 is significantly underexpressed in triple-negative breast cancer (TNBC) In our previous study, the lower expression of HRD1 was observed in breast cancer tissues compared to adjacent normal breast tissues [13]
Immunoblotting and RT-PCR showed that HRD1 is significantly underexpressed in TNBC cell lines in comparison with luminal breast cancer cells whether at protein or mRNA level (Fig. 1a), which was supported by quantitative RT-PCR analysis (Fig. 1b)
Summary
E3 ubiquitin ligase HRD1 (HMG-CoA reductase degradation protein 1, alias synoviolin with SYVN1 as the official gene symbol) was found downregulated and acting as a tumor suppressor in breast cancer, while the exact expression profile of HRD1 in different breast cancer subtypes remains unknown. As a type of highly heterogeneous malignancy, human breast cancer could be mainly divided into four molecular subtypes characterized by different gene expression patterns of several biomarkers, including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [2]. Recent studies showed that E3 ubiquitin ligases TRIM56 and RNF208 decrease cell migration and invasion of ovarian and breast cancer respectively by inducing polyubiquitination-mediated proteasomal degradation of Vimentin, suggesting that the suppression of Vimentin ameliorates metastasis in aggressive cancers [11, 12]. A tumor-suppressive effect of E3 ligase HRD1 on breast cancer was identified in our previous research [13], while the underlying mechanisms of HRD1 inhibiting breast cancer progression still need to be unraveled
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
