Abstract
Although the deregulation of lysine methyltransferase (su(var)-3–9, enhancer-of-zeste, trithorax) domain-containing protein 7/9 (SET7/9) has been identified in a variety of cancers, the potential role of SET7/9 and the molecular events in which it is involved in breast cancer remain obscure. Using the online Human Protein Atlas and GEO databases, the expression of SET7/9 was analyzed. Furthermore, we investigated the underlying mechanisms using chromatin immunoprecipitation-based deep sequencing (ChIP-seq) and quantitative ChIP assays. To explore the physiological role of SET7/9, functional analyses such as CCK-8, colony formation, and transwell assays were performed and a xenograft tumor model was generated with the human breast cancer cell lines MCF-7 and MDA-MB-231. Mass spectrometry, co-immunoprecipitation, GST pull-down, and ubiquitination assays were used to explore the mechanisms of SET7/9 function in breast cancer. We evaluated the expression of SET7/9 in different breast cancer cohorts and found that higher expression indicated worse survival times in these public databases. We demonstrated positive effects of SET7/9 on cell proliferation, migration, and invasion via the activation of Runt-related transcription factor 2 (RUNX2). We demonstrate that tripartite motif-containing protein 21 (TRIM21) physically associates with SET7/9 and functions as a major negative regulator upstream of SET7/9 through a proteasome-dependent mechanism and increased ubiquitination. Taken together, our data suggest that SET7/9 has a promoting role via the regulation of RUNX2, whereas TRIM21-mediated SET7/9 degradation acts as an anti-braking system in the progression of breast cancer.
Highlights
Breast cancer is one of the most common cancers among females worldwide; numerous advances in surgical resection, radiotherapy, chemotherapy, and neoadjuvant therapies have been made in recent decades, the morbidity and mortality of breast cancer remain high, and metastasis is still the major cause of cancer-related death[1,2,3]
By analyzing the Gene Expression Omnibus (GEO) GSE9893 and GSE12276 databases, the expression of SET7/9 was explored in different cohorts, and we noted that SET7/9 expression was significantly higher in breast tumor tissues and had negative effects on patient overall survival rates and local relapse times (Fig. 1b, c)
To elucidate the function of SET7/9 and RUNX2 and their roles in breast cancer cell migration and invasion, a Transwell assay was performed in MCF-7 or MDA-MB231 cells infected with SET7/9 short hairpin RNAs (shRNAs), and the results showed that the knockdown of SET7/9 robustly inhibited the migration activities of MCF-7 cells and the invasion capability of MDA-MB-231 cells
Summary
Breast cancer is one of the most common cancers among females worldwide; numerous advances in surgical resection, radiotherapy, chemotherapy, and neoadjuvant therapies have been made in recent decades, the morbidity and mortality of breast cancer remain high, and metastasis is still the major cause of cancer-related death[1,2,3]. Si et al Cell Death and Disease (2020)11:151 that SET7/9 is a potential novel candidate therapeutic target for breast cancer therapy. Like many other transcription factors, the upregulation of RUNX2 is regarded as an important contributor in breast cancer; the exact mechanism of RUNX2 is only beginning to be elucidated[18,19]. The dysregulation of TRIM21 contributes to the progression of human malignancies including breast cancer[21,22]. Our data provide compelling evidence that the degradation of SET7/9 by TRIM21 can be used to suppress breast cancer progression
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