USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment

Pulver, Tanya; Heilmann, Wiebke; Mooneyham, Ashley; Mullany, Sally A.; Zhao, Xianda; Shahi, Maryam; Richter, James; Klein, Molly; Chen, Liqiang; Ding, Rui; Konecny, Gottfried E.; Kommoss, Stefan; Winterhoff, Boris; Ghebre, Rahel; Bazzaro, Martina

doi:10.18632/oncotarget.8821

Cited by 35 publications

(22 citation statements)

References 36 publications

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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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Section: Discussionmentioning

confidence: 78%

USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1

et al. 2016

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“…35,36 The USP 14, one of the USP family enzymes, was shown to predict the endometrial cancer recurrence. 37 Although it was limited to the stage I endometrial cancer, it was a pioneer study suggesting the potential of drugs targeted against deubiquitinating enzymes in endometrial cancer.…”

Section: Discussionmentioning

confidence: 99%

High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients

Nakao

Hirakawa

Suwa

et al. 2018

Int J Gynecol Cancer

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“…Another study has shown that the UPS pathway plays an indispensable role in the regulation of mitochondrial energy metabolism by regulating the turnover of several mitochondrial oxidative phosphorylation (OXPHOS) proteins such as the succinate dehydrogenase subunit A (SDHA), the mitochondrial respiratory complex II [63,64]. Findings also indicate a mechanism of crosstalk between the proteasome and autophagy pathway [65][66][67][68][69]. This includes the degradation of synaptosomal-associated protein 29 (SNAP29) and syntaxin 17 (STX17) by the ubiquitin-independent 20S proteasome [70].…”

Section: The Ups and Tumor Metabolismmentioning

confidence: 99%

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

Zhang

Linder

Bazzaro

2020

Cancers

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Cancer cells are characterized by a higher rate of protein turnover and greater demand for protein homeostasis compared to normal cells. In this scenario, the ubiquitin-proteasome system (UPS), which is responsible for the degradation of over 80% of cellular proteins within mammalian cells, becomes vital to cancer cells, making the UPS a critical target for the discovery of novel cancer therapeutics. This review systematically categorizes all current reported small molecule inhibitors of the various essential components of the UPS, including ubiquitin-activating enzymes (E1s), ubiquitin-conjugating enzymes (E2s), ubiquitin ligases (E3s), the 20S proteasome catalytic core particle (20S CP) and the 19S proteasome regulatory particles (19S RP), as well as their mechanism/s of action and limitations. We also discuss the immunoproteasome which is considered as a prospective therapeutic target of the next generation of proteasome inhibitors in cancer therapies.Cancers 2020, 12, 902 2 of 34 core component of the nucleosome, which is critical for transcription and cell cycle, is recognized and linked by Lysine Residue 48 (K48) and further degraded by the proteasome [17,18]; DbpB (also named Y-box protein 1), a transcription factor, is reported to selectively recognize the Y-box promoter element. Studies showed that its terminal 105-amino-acid-long fragment is removed after a specific proteolytic cleavage by the proteasome complex [19,20]; NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) is located outside the nucleus and is reported to be involved in DNA transcription as well as cell survival [21,22]. The NF-κB p105 is the precursor of NF-κB p50. It is evident that NF-κB p105 is cleaved and selectively degraded at the C-terminus by proteasome, generating the active form of NF-κB p50 [23]. Products of UPS degradation can also be further degraded into single amino acids by aminopeptidases [24]. Aminopeptidases are the class of enzymes that catalyze the final steps in the ubiquitin-proteasome pathway by breaking down shorter peptides (<5 residues) into even smaller fragments [25]. Many, but not all, of aminopeptidases, are zinc metalloenzymes, such as leucine aminopeptidases (lAPs) and methionine aminopeptidases (metAPs) [26,27]. Studies showed that blocking the activity of the aminopeptidases by inhibitor of bestatin could generate a major accumulation of peptides which are ∼2-5 residues long [28].The 26S proteasome contains one/two 19S regulatory particles (19S RP) which mainly regulate the translocation of ubiquitinated proteins to the 20S CP and one 20S core particle (20S CP) in which proteolysis finally occurs [29,30]. In general, two main processes are associated with the process of degradation of proteins by the UPS: (1) tagging the to-be-degraded proteins by polyubiquitination (normally more than four ubiquitins), and (2) proteolytic degradation of the polyubiquitinated protein by the 26S proteasome complex [31,32]. Each step incorporates an intricate and complex spectrum of protein interaction...

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USP14 is a predictor of recurrence in endometrial cancer and a molecular target for endometrial cancer treatment

Cited by 35 publications

References 36 publications

USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1

USP14 regulates autophagy by suppressing K63 ubiquitination of Beclin 1

High Expression of Ubiquitin C-terminal Hydrolase L1 Is Associated With Poor Prognosis in Endometrial Cancer Patients

Drug Development Targeting the Ubiquitin–Proteasome System (UPS) for the Treatment of Human Cancers

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