Abstract
Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that harbors enriched cancer stem cell (CSC) populations in tumors. Conventional chemotherapy is a standard treatment for TNBC, but it spares the CSC populations, which cause tumor recurrence and progression. Therefore, identification of the core molecular pathway that controls CSC activity and expansion is essential for developing effective therapeutics for TNBC. In this study, we identify that USP2 deubiquitinating enzyme is upregulated in CSCs and is a novel regulator of CSCs. Genetic and pharmacological targeting of USP2 substantially inhibits the self-renewal, expansion and chemoresistance of CSCs. We show that USP2 maintains the CSC population by activating self-renewing factor Bmi1 and epithelial-mesenchymal transition through Twist upregulation. Mechanistically, USP2 promotes Twist stabilization by removing β-TrCP-mediated ubiquitination of Twist. Animal studies indicate that pharmacological inhibition of USP2 suppresses tumor progression and sensitizes tumor responses to chemotherapy in TNBC. Furthermore, the histological analyses reveal a positive correlation between USP2 upregulation and lymph node metastasis. Our findings together demonstrate a previously unrecognized role of USP2 in mediating Twist activation and CSC enrichment, suggesting that targeting USP2 is a novel therapeutic strategy to tackle TNBC.
Highlights
Treatment of triple-negative breast cancer (TNBC)remains challenging due to lack of effective targeted therapies, chemoresistance and high propensity toward metastasis[1]
ubiquitin-specific protease 2 (USP2) gene is upregulated in Triple-negative breast cancer (TNBC) and is essential for the expansion of cancer stem cell (CSC) in TNBC Advanced genomic profiling and hierarchical clustering have shown that breast tumors consist of at least five molecular subtypes: basal-like, human epidermal growth factor receptor 2 (HER2)-enriched, normal-like, luminal A and luminal B23
(see figure on previous page) Fig. 1 USP2 is upregulated and is essential for CSC self-renewal and expansion in TNBC. a cBioportal was used to access The Cancer Genome Atlas (TCGA) data for USP2 gene alternation from invasive carcinoma of basal-like breast cancer. b Real-time PCR analysis of USP2 mRNA levels in the non-CSC (ALDH−) and CSC (ALDH+) populations isolated from BT549 cells showed that USP2 gene expression is upregulated in CSCs. c, d Representative images and quantitative results of tumorsphere formation assay in BT549 (c), and MDA-MB-231 (d) cells stably infected with lentivirus containing shRNA targeting
Summary
Treatment of triple-negative breast cancer (TNBC)remains challenging due to lack of effective targeted therapies, chemoresistance and high propensity toward metastasis[1]. CSCs possess unlimited self-renewing and multipotency capacity that allows very few CSCs, including those post-treatment remnants, to give rise to differentiated cancer cell progeny and regrow heterogeneous tumors at the original (tumor recurrence) and/or distant organs (tumor metastases)[3,4]. Ubiquitination is a post-translational modification that attaches various kinds of ubiquitin molecules to protein substrates for regulating protein functions[5]. Diverse ubiquitin chains direct substrates toward different biological outcomes. Lysine (K) 48-linked ubiquitination, the most abundant polyubiquitination form in mammalian cells, targets proteins for proteasome-mediated degradation. K63-linked ubiquitination generally serves as a molecular platform that recruits adapter proteins for modulating protein trafficking, signaling transduction, endocytosis and lysosomal degradation. Aside from protein substrates, Liu et al, recently uncovered that the K63-linked ubiquitin chains can directly interact with
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