Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency

Ma, Yu‐Shui; Zhang, Yunjie; Luo, Pan; Long, Hui-Deng; Li, Liu; Yang, Haojie; Xie, Ruting; Jia, Chengyou; Lu, Gai‐Xia; Chang, Zhengyan; Zhang, Jiajia; Xue, Sheng; Lv, Zhongwei; Yu, Fei; Xia, Qing

doi:10.1016/j.omto.2019.12.013

Cited by 28 publications

(18 citation statements)

References 65 publications

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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: 86%

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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confidence: 86%

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

Liang

et al. 2020

Preprint

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“…IU1 is an active-site-directed thiol protease small molecule inhibitor that selectively inhibits Usp14 [215]. It has been recently reported that IU1-mediated inhibition of USP14 results in the increased ubiquitination of constitutive photo-morphogenesis 9 (COP9) signalosome subunit 5 (COPS5), a key negative p53 regulator, resulting in tumor regression of autochthonous T-lymphomas and sarcomas in p53-deficient mice without affecting normal tissues [216]. 3-Amino-2-keto-7H-thieno[2,3-b]pyridin-6-one derivative: 3-Amino-2-keto-7H-thieno[2,3-b] pyridin-6-one derivative is a UCHL1-targeting small molecule, discovered as a moderately potent non-competitive inhibitor that works by binding only to the Michaelis complex and not to free enzyme [218].…”

Section: Other Small Molecule Dub Inhibitorsmentioning

confidence: 99%

“…IU1 (1-[1-(4-fluorophenyl)-2,5-dimethylpyrrol-3-yl]-2-pyrrolidin-1-ylethanone): IU1 is an active-site-directed thiol protease small molecule inhibitor that selectively inhibits Usp14 [ 215 ]. It has been recently reported that IU1-mediated inhibition of USP14 results in the increased ubiquitination of constitutive photo-morphogenesis 9 (COP9) signalosome subunit 5 (COPS5), a key negative p53 regulator, resulting in tumor regression of autochthonous T-lymphomas and sarcomas in p53-deficient mice without affecting normal tissues [ 216 ].…”

Section: Drugs Targeting Dubs In Cancermentioning

confidence: 99%

Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Antao

Tyagi

Kim

et al. 2020

Cancers

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Since the discovery of the ubiquitin proteasome system (UPS), the roles of ubiquitinating and deubiquitinating enzymes (DUBs) have been widely elucidated. The ubiquitination of proteins regulates many aspects of cellular functions such as protein degradation and localization, and also modifies protein-protein interactions. DUBs cleave the attached ubiquitin moieties from substrates and thereby reverse the process of ubiquitination. The dysregulation of these two paramount pathways has been implicated in numerous diseases, including cancer. Attempts are being made to identify inhibitors of ubiquitin E3 ligases and DUBs that potentially have clinical implications in cancer, making them an important target in the pharmaceutical industry. Therefore, studies in medicine are currently focused on the pharmacological disruption of DUB activity as a rationale to specifically target cancer-causing protein aberrations. Here, we briefly discuss the pathophysiological and physiological roles of DUBs in key cancer-related pathways. We also discuss the clinical applications of promising DUB inhibitors that may contribute to the development of DUBs as key therapeutic targets in the future.

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“…Analysis. The DEGs between HCC samples and noncancerous tissues were determined using the EdgeR software package [33]. Fold change ðFCÞ ≥ 2 or ≤0.5 and p < 1:0E − 10 were chosen as elementary screening arguments for cluster analysis.…”

Section: Degs Screening and Survivalmentioning

confidence: 99%

MicroRNA-497-5p Is Downregulated in Hepatocellular Carcinoma and Associated with Tumorigenesis and Poor Prognosis in Patients

Jiang

Liu

et al. 2021

International Journal of Genomics

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Background. MicroRNAs (miRNAs) have been demonstrated to exhibit important regulatory roles in multiple malignancies, including hepatocellular carcinoma (HCC). hsa-miR-497-5p was reported to involve in cancer progression and poor prognosis in many kinds of tumors. However, the expression and its clinical significance of hsa-miR-497-5p in HCC remain unclear. Methods. In the present study, we investigated the expression of hsa-miR-497-5p in HCC and analyzed the correction of clinical features with prognosis. The expression levels of hsa-miR-497-5p and potential target genes were analyzed in HCC and adjacent noncancerous tissues using The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) datasets. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to analyze hsa-miR-497-5p levels in 328 HCC tissues and 30 paired adjacent noncancer tissues. Overall survival (OS) and progression-free survival (PFS) of patients with HCC were assessed using the Kaplan-Meier method and the log-rank test. Results. The hsa-miR-497-5p expression levels were decreased, and its target genes ACTG1, CSNK1D, PPP1CC, and BIRC5 were upregulated in HCC tissues compared with normal tissues. Lower levels of hsa-miR-497-5p expression and higher levels of the four target genes were significantly associated with higher tumor diameter. Moreover, patients with lower hsa-miR-497-5p expression and higher target genes levels had shorter OS. Conclusion. The expression levels of hsa-miR-497-5p may play an important regulatory role in HCC and are closely correlated with HCC progression and poor prognosis in patients. The hsa-miR-497-5p may be a specific therapeutic target for the treatment of HCC.

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Inhibition of USP14 Deubiquitinating Activity as a Potential Therapy for Tumors with p53 Deficiency

Cited by 28 publications

References 65 publications

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

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

Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

MicroRNA-497-5p Is Downregulated in Hepatocellular Carcinoma and Associated with Tumorigenesis and Poor Prognosis in Patients

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