Abstract:Nanog is a master pluripotency factor of embryonic stem cells (ESCs). Stable expression of Nanog is essential to maintain the stemness of ESCs. However, Nanog is a short-lived protein and quickly degraded by the ubiquitin-dependent proteasome system. Here we report that the deubiquitinase USP21 interacts with, deubiquitinates and stabilizes Nanog, and therefore maintains the protein level of Nanog in mouse ESCs (mESCs). Loss of USP21 results in Nanog degradation, mESCs differentiation and reduces somatic cell … Show more
“…Of note, USP21-deficient clones recovered from the HR defect after extended time in culture despite stable USP21 deletion (Supplementary Fig. 2C, D), pointing to compensatory mechanisms that may counteract deleterious consequences of USP21 loss, as reported previously in mice 28, 29 . Given that compensatory networks were found to be activated in response to deleterious mutations rather than gene knockdown 30 , subsequent experiments were performed under conditions of acute USP21 depletion via RNAi, or in early-stage USP21 KO cells.Fig.…”
Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division. Modulating repair factor function, thus, provides a promising strategy to manipulate malignant growth. Here, we identify the ubiquitin-specific protease USP21 as a positive regulator of BRCA2, a key mediator of DNA repair by homologous recombination. USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. As a result, depletion of USP21 decreases homologous recombination efficiency, causes an increase in DNA damage load and impairs tumor cell survival. Importantly, BRCA2 overexpression partially restores the USP21-associated survival defect. Moreover, we show that USP21 is overexpressed in hepatocellular carcinoma, where it promotes BRCA2 stability and inversely correlates with patient survival. Together, our findings identify deubiquitination as a means to regulate BRCA2 function and point to USP21 as a potential therapeutic target in BRCA2-proficient tumors.
“…Of note, USP21-deficient clones recovered from the HR defect after extended time in culture despite stable USP21 deletion (Supplementary Fig. 2C, D), pointing to compensatory mechanisms that may counteract deleterious consequences of USP21 loss, as reported previously in mice 28, 29 . Given that compensatory networks were found to be activated in response to deleterious mutations rather than gene knockdown 30 , subsequent experiments were performed under conditions of acute USP21 depletion via RNAi, or in early-stage USP21 KO cells.Fig.…”
Tumor growth relies on efficient DNA repair to mitigate the detrimental impact of DNA damage associated with excessive cell division. Modulating repair factor function, thus, provides a promising strategy to manipulate malignant growth. Here, we identify the ubiquitin-specific protease USP21 as a positive regulator of BRCA2, a key mediator of DNA repair by homologous recombination. USP21 interacts with, deubiquitinates and stabilizes BRCA2 to promote efficient RAD51 loading at DNA double-strand breaks. As a result, depletion of USP21 decreases homologous recombination efficiency, causes an increase in DNA damage load and impairs tumor cell survival. Importantly, BRCA2 overexpression partially restores the USP21-associated survival defect. Moreover, we show that USP21 is overexpressed in hepatocellular carcinoma, where it promotes BRCA2 stability and inversely correlates with patient survival. Together, our findings identify deubiquitination as a means to regulate BRCA2 function and point to USP21 as a potential therapeutic target in BRCA2-proficient tumors.
“…As the crucial role of Nanog in stemness maintenance of embryonic stem cell and cancer stem cell has been well established and extensively studied by other groups (Song et al, 2017; Jin et al, 2016; Noh et al, 2012; Chambers et al, 2003; Mitsui et al, 2003), we intend to further pinpoint whether SPOP deficiency upregulates prostate CSC properties in a Nanog-dependent manner. To this end, we examined the effects of SPOP deficiency in the presence or absence of Nanog on various prostate CSC traits.…”
SUMMARY
Frequent SPOP mutation defines the molecular feature underlying one of seven sub-types of human prostate cancer (PrCa). However, it remains largely elusive how SPOP functions as a tumor suppressor in PrCa. Here, we report that SPOP suppresses stem cell traits of both embryonic stem cells and PrCa cells through promoting Nanog poly-ubiquitination and subsequent degradation. Mechanistically, Nanog, but not other pluripotency-determining factors including Oct4, Sox2, and Klf4, specifically interacts with SPOP via a conservative degron motif. Importantly, cancer-derived mutations in SPOP or at the Nanog-degron (S68Y) disrupt SPOP-mediated destruction of Nanog, leading to elevated cancer stem cell traits and PrCa progression. Notably, we identify the Pin1 oncoprotein as an upstream Nanog regulator that impairs its recognition by SPOP and thereby stabilizes Nanog. Thus, Pin1 inhibitors promote SPOP-mediated destruction of Nanog, which provides the molecular insight and rationale to use Pin1 inhibitor(s) for targeted therapies of PrCa patients with wild-type SPOP.
“…USP21 was reported to deubiquitinate and stabilize Nanog as well as be recruited by Nanog to deubiquitinate H2A, thus facilitating Nanog’s target gene expression (Jin et al, 2016). In addition, the phosphorylation of Sox2 protein by AKT1 enhances the stabilization of Sox2 by antagonizing protein degradation and promotes the self-renewal capacity of mouse ESCs, while Set7 monomethylates Sox2 to induce the recruitment of E3 ligase WWP2 which mediate ubiquitination and degradation of Sox2 (Fang et al, 2014).…”
Section: Dubs In Regulation Of Critical Steps In Tumor Metastasismentioning
Malfunction of ubiquitin-proteasome system is tightly linked to tumor formation and tumor metastasis. Targeting the ubiquitin-pathway provides a new strategy for anti-cancer therapy. Despite the parts played by ubiquitin modifiers, removal of ubiquitin from the functional proteins by the deubiquitinating enzymes (DUBs) plays an important role in governing the multiple steps of the metastatic cascade, including local invasion, dissemination, and eventual colonization of the tumor to distant organs. Both deregulated ubiquitination and deubiquitination could lead to dysregulation of various critical events and pathways such as apoptosis and epithelial-mesenchymal transition (EMT). Recent TCGA study has further revealed the connection between mutations of DUBs and various types of tumors. In addition, emerging drug design targeting DUBs provides a new strategy for anti-cancer therapy. In this review, we will summarize the role of deubiquitination and highlight the recent discoveries of DUBs with regards to multiple metastatic events including anti-apoptosis pathway and EMT. We will further discuss the regulation of deubiquitination as a novel strategy for anti-cancer therapy.
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