Abnormally elevated USP37 expression in breast cancer stem cells regulates stemness, epithelial-mesenchymal transition and cisplatin sensitivity

Background: Recent studies have indicated that deubiquitinating Enzymes (DUBs) are related to the stem-cell pathway network and chemo-resistance in Cancer. Ubiquitin-specific peptidase 37 (USP37), a novel DUB, was identified to be a potential factor associated with tumor progression. However, the biological functions of USP37 in breast Cancer remain unclear.

Methods: The distribution of USP37 expression in breast Cancer and the correlation between USP37 expression and the overall survival rate were detected by The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was utilized to evaluate potential mechanism of USP37 in breast Cancer. The USP37 expression in breast Cancer tissues and breast Cancer cell lines were detected by immunohistochemistry and western blotting. Sorting of breast Cancer Stem Cells (BCSCs) were by using MACS assay. In vitro and in vivo assays were performed to examine the biological functions of USP37 in breast Cancer cells. MG132, CHX chase, immunofluorescence staining and co-immunoprecipitation assays were used to test the interaction between USP37 and Gli-1.

Results: Bioinformatics analysis demonstrated that USP37 gene was elevated in breast Cancer tissues and its overexpression was strongly correlated with the increased mortality rate. GSEA analysis showed that USP37 expression was positively associated with cell growth and metastasis while negatively related to cell Apoptosis in the TCGA breast Cancer samples. USP37 expression was elevated in breast Cancer tissues and breast Cancer cell lines. Moreover, we also detected that USP37 was overexpressed in BCSCs. USP37 regulated the ability of cell invasion, epithelial-mesenchymal transition (EMT), stemness and cisplatin sensitivity in breast Cancer cell lines. Additionally, USP37 knockdown inhibited tumorigenicity and increased Anticancer effect of cisplatin in vivo. Knockdown of USP37 significantly decreased Hedgehog (Hh) pathway components Smo and Gli-1. Gli-1 was stabilized by USP37 and they interacted with each other. Further studies indicated that USP37 knockdown could inhibit the stemness, cell invasion and EMT in breast Cancer via downregulation of Hh pathway.

Conclusions: These findings reveal that USP37 is highly expressed in BCSCs and is correlated with poor prognosis in breast Cancer patients. USP37 can regulate the stemness, cell invasion and EMT via Hh pathway, and decreased USP37 confers sensitivity to cisplatin in breast Cancer cells. USP37 is required for the regulation of breast Cancer progression, as well as a critical target for clinical treatment of breast Cancer.