Inhibition of USP2 eliminates cancer stem cells and enhances TNBC responsiveness to chemotherapy

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.

Targeting Cancer Stem Cells in Triple-Negative Breast Cancer

“…USP2 was identified to be up-regulated in patients with metastasis, and then upon further clinicopathological assessment, USP2 enrichment was detected in TNBC relative to that in non-TNBC [92]. He et al found that silencing USP2 in TNBC reduced mammosphere formation and chemoresistance [93]. Their study showed that USP2 stabilized Twist by cleaving proteolytic ubiquitination, and Twist increased the transcription of Bmi1, which is a polycomb complex protein that controls the self-renewal and pluripotency of stem cells [93].…”

“…He et al found that silencing USP2 in TNBC reduced mammosphere formation and chemoresistance [93]. Their study showed that USP2 stabilized Twist by cleaving proteolytic ubiquitination, and Twist increased the transcription of Bmi1, which is a polycomb complex protein that controls the self-renewal and pluripotency of stem cells [93]. Davis et al developed the USP2-specific inhibitor ML364, which directly binds and inhibits the enzymatic activity of USP2 [94].…”

“…Davis et al developed the USP2-specific inhibitor ML364, which directly binds and inhibits the enzymatic activity of USP2 [94]. ML364 efficiently inhibited the self-renewing function of TNBC cells and reduced tumor growth in vivo in xenograft models [93].…”

Mechanistic Pathways of Malignancy in Breast Cancer Stem Cells

“…Finally, hedgehog signaling drives to stemness, invasion, and EMT of BCSCs (103). In addition, USP2 activates Bmi1 and EMT by stabilizing Twist through removing ubiquitylation mediated by beta-transducin repeats-containing proteins (β-TrCP), a cellular E3 ubiquitin ligase (104).…”

Bioinformatics analysis and verification of molecular targets in ovarian cancer stem-like cells

“…Therefore, eradication of CSCs is a potential therapeutic avenue to increase the survival rate of EOC patients. Recently, studies have shown that targeting key molecular players and genetic aberrations in CSCs using small molecule inhibitors, including rapamacyin and triciribine can eradicate CSCs in brain tumors and improve overall survival in glioblastoma and neuroblastoma patients [ 4 , 8 , 9 , 10 , 11 , 12 ]. Identifying the molecular signature of ovarian CSCs will provide a novel therapeutic strategy to selectively target this subpopulation of cells and improve overall survival.…”