Ubiquitin-specific protease 14 (USP14) regulates cellular proliferation and apoptosis in epithelial ovarian cancer

Wang, Yingying; Wang, Juan; Zhong, Jun; Deng, Yan; Xi, Qinghua; He, Song; Yang, Shuyun; Jiang, Lifei; Huang, Menghui; Tang, Chunhui; Liu, Rong

doi:10.1007/s12032-014-0379-8

Cited by 62 publications

(56 citation statements)

References 24 publications

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“…USP14 is strongly expressed in MM cells (Supplementary Fig. 4a) and has also been reported to be overexpressed in other malignancies such as ovarian and hepatocellular carcinoma3435. We found that knock-down of either USP14 or UCHL5 in multiple myeloma cells resulted in loss of cell viability, consistent with our previous results36 and those of other investigators using hepatocellular carcinoma and ovarian cancer cells3435.…”

Section: Discussionsupporting

confidence: 91%

The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

Wang

Mazurkiewicz

Hillert

et al. 2016

Sci Rep

129

141

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Inhibition of deubiquitinase (DUB) activity is a promising strategy for cancer therapy. VLX1570 is an inhibitor of proteasome DUB activity currently in clinical trials for relapsed multiple myeloma.Here we show that VLX1570 binds to and inhibits the activity of ubiquitin-specific protease-14 (USP14) in vitro, with comparatively weaker inhibitory activity towards UCHL5 (ubiquitin-C-terminal hydrolase-5). Exposure of multiple myeloma cells to VLX1570 resulted in thermostabilization of USP14 at therapeutically relevant concentrations. Transient knockdown of USP14 or UCHL5 expression by electroporation of siRNA reduced the viability of multiple myeloma cells. Treatment of multiple myeloma cells with VLX1570 induced the accumulation of proteasome-bound high molecular weight polyubiquitin conjugates and an apoptotic response. Sensitivity to VLX1570 was moderately affected by altered drug uptake, but was unaffected by overexpression of BCL2-family proteins or inhibitors of caspase activity. Finally, treatment with VLX1570 was found to lead to extended survival in xenograft models of multiple myeloma. Our findings demonstrate promising antiproliferative activity of VLX1570 in multiple myeloma, primarily associated with inhibition of USP14 activity.A diverse set of cellular processes such as cell cycle progression, DNA repair, metabolism and cell survival are dynamically controlled by the synthesis and degradation of protein regulators. In eukaryotic cells the regulated degradation of proteins is controlled mainly by the ubiquitin proteasome system (UPS)1 . The UPS is composed of a destruction tag in the form of the small protein ubiquitin and the 26S proteasome, a large multi-subunit proteolytic complex that specifically degrades ubiquitin tagged proteins into small peptides. The proteolytic activities of the proteasome reside within the 20S core particle (20S CP), a barrel like structure composed of 4 stacked heptameric rings (α 7 β 7 β 7 α 7 ) associated with one or two 19S regulatory particles (19S RP) 2,3 . Protein degradation begins with the covalent tagging of substrates with multi-ubiquitin chains, an event that initiates traffic to the proteasome and subsequent capture by highly specific ubiquitin receptors located within the 19S RP. Once bound, substrates undergo a sequence of modifications including de-ubiquitination by proteasome associated deubiquitinases (DUBs), unwinding by the 19S RP ATPases and finally translocation into the 20S CP where they are degraded 4 . Several roles for proteasome DUBs have been proposed including a rescue mechanism for improperly or poorly ubiquitinated substrates, maintenance of ubiquitin homeostasis by ubiquitin

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Section: Discussionsupporting

confidence: 91%

The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

Wang

Mazurkiewicz

Hillert

et al. 2016

Sci Rep

129

141

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“…Inhibition of ІRE1 signaling enzyme function in U87 glioma cells increased effect of glutamine deprivation on the expression of USP1 gene and introduced sensitivity of USP4 and USP14 genes to this condition. A decreased level of USP1, USP4, and USP14 mRNA expression upon glutamine deprivation agrees well with functional role of these enzymes and suppression of glioma cell proliferation, because there is data that USP1 targeting impedes GBM growth and that USP4 and USP14 regulate cellular proliferation and apoptosis [16,18,23].…”

Section: Resultssupporting

confidence: 65%

“…In agreement, microRNA-191 mediated lower protein level of USP10 has been demonstrated to promote pancreatic cancer progression [21]. It was shown that USP14 is a tumor promoting peptidase, its phosphorylation and activation by Akt not only regulates the ubiquitin-proteasome system, but also promotes tumor progression through regulation of cellular proliferation and apoptosis of cancer cells [23]. Inhibition of USP14 could be used as potential anti-cancer therapeutic strategy.…”

mentioning

confidence: 84%

Expression of ubiquitin specific peptidase and ATG7 genes in U87 glioma cells upon glutamine deprivation

Halkin¹,

Minchenko²,

Riabovol³

et al. 2017

Ukr.Biochem.J

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We have studied the effect of glutamine deprivation on the expression of genes encoding for ubiquitin specific peptidases (usP) [4][5][6]. A better knowledge of tumor respon ses to glutamine deprivation condition is required to elaborate new therapeutical strategies of cell sensibilization, based on the blockade of survival mechanisms.Ubiquitin is a highly conserved protein involved in regulation of intracellular protein breakdown, cell cycle regulation, chromatin remodeling, and stress response. It is released from degraded proteins by disassembly of the polyubiquitin chains, which is mediated by ubiquitin-specific proteases, members of the ubiquitin-specific processing family of proteases for deubiquitination of proteins [7][8][9]. E3 ubiquitin ligases and deubiquitylases play an important role in cancer [7,10,11]. Our previous results demonstrated possible interaction/cross-talk between unfolding protein response signaling and ubiquitin system during adjustment to episodes of hypoxia during tumor development [12]. Ubiquitin specific peptidases (USPs) and ubiquitin activating enzyme E1-like protein/autophagy related 7 (GSA7/ ATG7) are involved in cancer cells survival and progression [13][14][15]. USP1 and USP7 are responsible for deubiquitination of mono-ubiquitinated PCNA (proliferating cell nuclear antigen), which activates error-prone DNA polymerases and controls an oxidative-stress-induced mutagenesis in human cells [13]. Decreased levels of USP1 in cancer cells have been implicated in lung and glioblastoma tumors growth and progression [14,16]. There is data that serine phosphorylation is critical for the activity of USP1 and its interaction with WD40-repeat protein UAF1; while two nuclear localization signals

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“…These results suggest that activated Akt in Pten-negative cancer cells might be able to stabilize a significant portion of the proteome by inhibiting both UPS and autophagy through regulating USP14 to promote tumorigenesis. Consistent with this possibility, increased expression of USP14 has been found in a variety of cancers, including multiple myeloma (Tian et al 2014), colorectal cancer (Shinji et al 2006), lung cancer (Wu et al 2013), epithelial ovarian cancer (Wang et al 2015), and endometrial cancer (Vogel et al 2016). Future studies will be needed to elucidate the functional role of elevated USP14 expression in tumorigenesis.…”

Section: Discussionmentioning

confidence: 78%

USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1

et al. 2016

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The ubiquitin-proteasome system (UPS) and autophagy are two major intracellular degradative mechanisms that mediate the turnover of complementary repertoires of intracellular proteomes. Simultaneously activating both UPS and autophagy might provide a powerful strategy for the clearance of misfolded proteins. However, it is not clear whether UPS and autophagy can be controlled by a common regulatory mechanism. K48 deubiquitination by USP14 is known to inhibit UPS. Here we show that USP14 regulates autophagy by negatively controlling K63 ubiquitination of Beclin 1. Furthermore, we show that activation of USP14 by Akt-mediated phosphorylation provides a mechanism for Akt to negatively regulate autophagy by promoting K63 deubiquitination. Our study suggests that Akt-regulated USP14 activity modulates both proteasomal degradation and autophagy through controlling K48 and K63 ubiquitination, respectively. Therefore, regulation of USP14 provides a mechanism for Akt to control both proteasomal and autophagic degradation. We propose that inhibition of USP14 may provide a strategy to promote both UPS and autophagy for developing novel therapeutics targeting neurodegenerative diseases.[Keywords: USP14; autophagy; Beclin 1; Akt] Supplemental material is available for this article. Autophagy and the ubiquitin-proteasome system (UPS) are two major intracellular degradative mechanisms that function in a complementary manner. UPS mediates the degradation of short-lived proteins conjugated with K48 ubiquitin chains (Komander and Rape 2012). On the other hand, autophagy mediates the turnover of long-lived proteins and intracellular organelles encapsulated in autophagosomes that eventually fuse with lysosomes to allow degradation by lysosomal proteases. Ubiquitination is also involved as a signaling mechanism in targeting both protein substrates and organelles such as depolarized mitochondria for degradation by autophagy (Sarraf et al. 2013;Ordureau et al. 2014). Ubiquitination of protein substrates is a reversible process, as ubiquitin chains can be removed by deubiquitinating enzymes (DUBs). Deubiquitination is an important negative regulatory mechanism for reducing the levels of protein ubiquitination. Ubiquitin-specific protease-14 (USP14), a DUB reversibly associated with the proteasome, has been shown to negatively regulate the activity of proteasomes by trimming K48 ubiquitin chains on proteasome-bound substrates (Borodovsky et al. 2001;Koulich et al. 2008;Lee et al. 2010). USP14 can also be activated by Akt-mediated phosphorylation, which promotes its deubiquitinating activity for both K48 and K63 ubiquitin linkages (Xu et al. 2015a). The activity of USP14 in deubiquitinating K63 ubiquitin linkages is likely to be physiologically relevant, as inhibition of USP14 in vivo leads to increases in the levels of K63-linked ubiquitin conjugates in both spinal cords and neurons (Vaden et al. 2015). However, the mechanism by which USP14 regulates K63 ubiquitination in control of cellular processes and its functional significance are...

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Ubiquitin-specific protease 14 (USP14) regulates cellular proliferation and apoptosis in epithelial ovarian cancer

Cited by 62 publications

References 24 publications

The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

The proteasome deubiquitinase inhibitor VLX1570 shows selectivity for ubiquitin-specific protease-14 and induces apoptosis of multiple myeloma cells

Expression of ubiquitin specific peptidase and ATG7 genes in U87 glioma cells upon glutamine deprivation

USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1

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