USP14 Inhibition Regulates Tumorigenesis by Inducing Autophagy in Lung Cancer In Vitro

Han, Kyung Ho; Kwak, Minseok; Lee, Tae Hyeong; Park, Minsoo; Jeong, In-ho; Kim, Min Ji; Jin, Jun‐O; Lee, Peter Chang-Whan

doi:10.3390/ijms20215300

Cited by 38 publications

(38 citation statements)

References 23 publications

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“…It has also been reported that IU1-47 causes a degradation of wild-type tau in neurons at a significantly higher rate than IU1 due to its extra targets on lysine-174 in tau protein, which may contribute to the higher specificity and efficacy [227]. A recent study has tested IU1-47 in lung cancer and proved that the inhibition of proteasome USP14 by IU1-47 could significantly decrease cell proliferation, migration, and invasion in lung cancer [130].…”

Section: Inhibitors Of 19s Proteasome Regulatory Particlesmentioning

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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Section: Inhibitors Of 19s Proteasome Regulatory Particlesmentioning

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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“…Though USP14 is more pronounced for its therapeutic potential in cancer (Shinji et al, 2006;Liao et al, 2018;Han et al, 2019), its role in neurodegenerative disorders is also known (Boselli et al, 2017;Min et al, 2017;Chakraborty et al, 2018). It is well accepted that the influence of USP14 on proteasome complex activity is inversely correlated (Lee et al, 2010;Kim and Goldberg, 2017).…”

Section: Discussionmentioning

confidence: 99%

USP14 as a Therapeutic Target Against Neurodegeneration: A Rat Brain Perspective

Banerjee

Roy

Mondal

et al. 2020

Front. Cell Dev. Biol.

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In the recent past, many of the deubiquitinases (DUB) were found to modulate mitochondrial clearance or mitophagy and thus they are currently projected as therapeutic targets against neurodegeneration. Among these DUBs, USP14 stands at a distinctive juncture, since it can influence both proteasome complex activity and autophagy process. USP14 interference can enhance mitochondrial clearance and thus can protect Parkinsonian phenotypes in Drosophila model. However, in higher animal models of neurodegenerative disorders, evaluation of the protective role of USP14 is yet to be done. In this perspective, we pointed out a few of the major considerations that should be classified before designing experiments to evaluate the therapeutic potential of this DUB in rodent models of neurodegeneration. These are mainly: level of USP14 in the concerned brain region and how the level alters in the model system. Because USP14 mediated mitophagy is Prohibitin2 dependent, the anticipated impact of this protein in this aspect is also discussed. To illustrate our view, we show that USP14 levels increases in adult rat brain substantia nigra (SN) and cerebellum compared to the young ones. We also depict that rotenone treatment can immediately lead to increased SN specific USP14 levels. Our perception thus portrays USP14 as a therapeutic target, especially for addressing SN specific neurodegeneration in adult rat brain, but may vary with the disease model.

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“…However, tests using IU1 in animal models have yielded mixed results. Consistent with promotion of proteasomal degradation of damaged proteins by USP14 inhibition, IU1 and exosomal miR124, both suppress USP14, were shown to protect against cerebral ischemia/reperfusion injury in mice [23,24], but USP14 inhibition was also shown to induce cell death and effectively treat malignancies in animal models [25,26]. Moreover, the axJ mouse that is homozygous for an apparently loss-of-function mutation of Usp14 and with a reduction of USP14 protein by 95%, shows severe neuromuscular abnormalities at 2-3 weeks and dies between 6-10 weeks of age [27].…”

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confidence: 79%

USP14 Haploinsufficiency Ameliorates Alzheimer’s Disease-Like Pathology in APP/PS1 Mice

Liang

et al. 2020

Preprint

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Background: Alzheimer's disease (AD) is the most common cause of dementia; its main pathological features are neurofibrillary tangles (NFTs) consisting of hyperphosphorylated microtubule-associated protein (Tau) in the cell and extracellular beta-amyloid protein (Aβ)-based senile plaques (SP). The ubiquitin-proteasome system (UPS) is the main pathway for protein degradation in cells. Proteasome malfunction exists in AD patients and may promote the progression of the disease. USP14 is a deubiquitinating enzyme associated with the 19S proteasome. Functional inhibition of USP14 was shown to enhance proteasome proteolytic function, but no reported study has investigated the impact of genetic inhibition of USP14 on AD.Methods: Mice with heterozygous knockout of the Usp14 gene (USP14+/-) were generated and cross-bred with the APP/PS1 transgenic mice, the resultant offspring littermates were subjected to basal survival and growth analyses, and comparison of AD-like pathologies as detected with biochemical and histopathological methods and of cognitive function as assessed with the Morris water maze tests. Results:USP14 mRNA and protein levels in USP14+/- mice were decreased by ~50% compared with USP14+/+mice. The increases of total, K48 or K63 linked ubiquitinated proteins in APP/PS1 mouse brains were abolished in APP/PS1::USP14+/- mice. The increases in Aβ deposition and AD-associated phosphorylated Tau, senile plagues and neurofibrillary tangles, as well as spatial learning and memory decline induced by APP/PS1 were significantly attenuated in APP/PS1 mice. Conclusions: This study demonstrates that global knocking down USP14 protein expression by 50% is tolerable by mice and exhibits marked protection against AD-like pathologies in a widely used AD mouse model, favoring the exploration of moderate inhibition ofUSP14 as a potentially novel and viable therapy against AD.

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USP14 Inhibition Regulates Tumorigenesis by Inducing Autophagy in Lung Cancer In Vitro

Cited by 38 publications

References 23 publications

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

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

USP14 as a Therapeutic Target Against Neurodegeneration: A Rat Brain Perspective

USP14 Haploinsufficiency Ameliorates Alzheimer’s Disease-Like Pathology in APP/PS1 Mice

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