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

Abstract

BackgroundRecent 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.MethodsThe 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.ResultsBioinformatics 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.ConclusionsThese 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.Electronic supplementary materialThe online version of this article (10.1186/s13046-018-0934-9) contains supplementary material, which is available to authorized users.

The Deubiquitinating Enzyme USP37 Stabilizes CHK1 to Promote the Cellular Response to Replication Stress

“…Consistent with the idea that the USP37-depleted cells are undergoing replication stress these cells showed enhanced induction of γH2AX and 53BP1 foci after treatment with aphidicolin along with loss of proliferative capacity upon exposure to multiple forms of replication stress. These results are consistent with a recent study that found USP37-depleted cells are more sensitive to camptothecin (Qin et al, 2018). USP37 has been implicated in the regulation of DNA repair, primarily homologous recombination (HR) (Typas et al, 2015).…”

USP32 promotes tumorigenesis and chemoresistance in gastric carcinoma via upregulation of SMAD2

“…Song et al reported that deubiquitylating enzyme Rpn11 can enhance the chemosensitivity of bortezomib in multiple myeloma cells [35]. Other than that, Qin et al demonstrated that silencing of USP37 can reduce resistance to cisplatin-targeting therapies in breast cancer [36]. In this regard, we also observed that USP32 downregulation could decrease the cisplatinresistance in GC cells, suggesting the involvement of USP32 in drug resistance.…”

USP37 Promotes Lung Cancer Cell Migration by Stabilizing Snail Protein via Deubiquitination

“…Recent data have reported that the expression of USP37 is elevated in various types of cancers, including breast and lung cancers, and is strongly correlated with the increased mortality rate and metastasis (Pan et al, 2015;Qin et al, 2018). USP37 is found to participate in many biologic processes such as cell growth, mitosis, DNA replication, migration, and EMT, as well as stemness and chemoresistance.…”

“…As such, a number of substrates have been identified for USP37 to commensurate its biological functions. For example, USP37 can interact with Hedgehog pathway components Smo and Gli-1 to stabilize these proteins and is essential for stemness maintenance, cell invasion, and EMT in breast cancer (Qin et al, 2018). In lung cancer cells, USP37 promotes cell proliferation and enhances the Warburg effect by directly interacting with c-Myc to deubiquitinate c-Myc (Pan et al, 2015).…”