Deubiquitylating enzymes and drug discovery: emerging opportunities

Nature Reviews Drug Discovery, Год журнала: 2017, Номер 17(1), С. 57 - 78

Опубликована: Сен. 29, 2017

Язык: Английский

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Targeting ubiquitin specific proteases (USPs) in cancer immunotherapy: from basic research to preclinical application

Journal of Experimental & Clinical Cancer Research, Год журнала: 2023, Номер 42(1)

Опубликована: Сен. 1, 2023

Tumors have evolved in various mechanisms to evade the immune system, hindering antitumor response and facilitating tumor progression. Immunotherapy has become a potential treatment strategy specific different cancer types by utilizing multifarious molecular enhance against tumors. Among these mechanisms, ubiquitin-proteasome system (UPS) is significant non-lysosomal pathway protein degradation, regulated deubiquitinating enzymes (DUBs) that counterbalance ubiquitin signaling. Ubiquitin-specific proteases (USPs), largest DUB family with strongest variety, play critical roles modulating cell function, regulating response, participating antigen processing presentation during According recent studies, expressions of some USP members cells are involved escape microenvironment. This review explores targeting USPs as new approach for immunotherapy, highlighting basic preclinical studies investigating applications inhibitors. By providing insights into structure function immunity, this aims at assisting developing therapeutic approaches enhancing immunotherapy efficacy.

Язык: Английский

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From Discovery to Bedside: Targeting the Ubiquitin System

Cell chemical biology, Год журнала: 2018, Номер 26(2), С. 156 - 177

Опубликована: Дек. 13, 2018

Язык: Английский

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USP9X regulates centrosome duplication and promotes breast carcinogenesis

Nature Communications, Год журнала: 2017, Номер 8(1)

Опубликована: Март 31, 2017

Abstract Defective centrosome duplication is implicated in microcephaly and primordial dwarfism as well various ciliopathies cancers. Yet, how the biogenesis regulated remains poorly understood. Here we report that X-linked deubiquitinase USP9X physically associated with centriolar satellite protein CEP131, thereby stabilizing CEP131 through its activity. We demonstrate an integral component of required for biogenesis. Loss-of-function impairs gain-of-function promotes amplification chromosome instability. Significantly, overexpressed breast carcinomas, level expression correlated higher histologic grades cancer. Indeed, USP9X, regulation abundance, carcinogenesis. Our experiments identify important regulator uncover a critical role USP9X/CEP131 carcinogenesis, supporting pursuit potential targets cancer intervention.

Язык: Английский

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Advances in Deubiquitinating Enzyme Inhibition and Applications in Cancer Therapeutics

Cancers, Год журнала: 2020, Номер 12(6), С. 1579 - 1579

Опубликована: Июнь 15, 2020

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

Язык: Английский

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Emerging Role of Ubiquitination in the Regulation of PD-1/PD-L1 in Cancer Immunotherapy

Molecular Therapy, Год журнала: 2021, Номер 29(3), С. 908 - 919

Опубликована: Янв. 1, 2021

A growing amount of evidence suggests that ubiquitination and deubiquitination programmed death 1 (PD-1)/programmed death-ligand (PD-L1) play crucial roles in the regulation PD-1 PD-L1 protein stabilization dynamics. PD-1/PD-L1 is a major coinhibitory checkpoint pathway modulates immune escape cancer patients, its engagement inhibition has significantly reshaped landscape tumor clearance. The abnormal influence PD-1/PD-L1-mediated immunosuppression. In this review, we describe ubiquitination- deubiquitination-mediated modulation signaling through variety E3 ligases deubiquitinating enzymes (DUBs). Moreover, briefly expound on anticancer potential some agents target related ligases, which further modulate cancers. Therefore, review reveals development highly promising therapeutic approach for immunotherapy by targeting ubiquitination.

Язык: Английский

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De Novo Loss-of-Function Mutations in USP9X Cause a Female-Specific Recognizable Syndrome with Developmental Delay and Congenital Malformations

The American Journal of Human Genetics, Год журнала: 2016, Номер 98(2), С. 373 - 381

Опубликована: Янв. 28, 2016

Язык: Английский

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Genomic analysis of low‐grade serous ovarian carcinoma to identify key drivers and therapeutic vulnerabilities

The Journal of Pathology, Год журнала: 2020, Номер 253(1), С. 41 - 54

Опубликована: Сен. 24, 2020

Low-grade serous ovarian carcinoma (LGSOC) is associated with a poor response to existing chemotherapy, highlighting the need perform comprehensive genomic analysis and identify new therapeutic vulnerabilities. The data presented here represent largest genetic study of LGSOCs date (n = 71), analysing 127 candidate genes derived from whole exome sequencing cohorts generate mutation copy-number variation data. Additionally, immunohistochemistry was performed on our LGSOC cohort assessing oestrogen receptor, progesterone TP53, CDKN2A status. Targeted identified 47% cases mutations in key RAS/RAF pathway (KRAS, BRAF, NRAS), as well putative novel driver including USP9X (27%), MACF1 (11%), ARID1A (9%), NF2 (4%), DOT1L (6%), ASH1L (4%). Immunohistochemistry evaluation revealed frequent oestrogen/progesterone receptor positivity (85%), along protein loss (10%) overexpression which were linked shorter disease outcomes. Indeed, 90% samples harboured at least one potentially actionable alteration, 19/71 (27%) predictive clinical benefit standard treatment, either another cancer's indication or specifically. In addition, we validated ubiquitin-specific protease 9X (USP9X), chromosome X-linked substrate-specific deubiquitinase tumour suppressor, relevant target for LGSOC. Our highlighted that there an addiction limited number unique 'driver' aberrations could be translated into improved paths. © 2020 Pathological Society Great Britain Ireland. Published by John Wiley & Sons, Ltd.

Язык: Английский

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USP9X deubiquitinates ALDH1A3 and maintains mesenchymal identity in glioblastoma stem cells

Journal of Clinical Investigation, Год журнала: 2019, Номер 129(5), С. 2043 - 2055

Опубликована: Апрель 7, 2019

The mesenchymal (MES) subtype of glioblastoma (GBM) stem cells (GSCs) represents a subpopulation cancer that are notorious for their highly aggressive nature and resistance to conventional therapy. Aldehyde dehydrogenase 1A3 (ALDH1A3) has been recently suggested as key determinant the maintenance MES features GSCs. However, mechanisms underpinning aberrant ALDH1A3 expression remain elusive. Here, we identified ubiquitin-specific protease 9X (USP9X) bona fide deubiquitinase in USP9X interacted with, depolyubiquitylated, stabilized ALDH1A3. Moreover, showed FACS-sorted USP9Xhi were enriched GSCs with high activity potent tumorigenic capacity. Depletion markedly downregulated ALDH1A3, resulting loss self-renewal capacity GSCs, which could be largely rescued by ectopic Furthermore, demonstrated inhibitor WP1130 induced degradation marked therapeutic efficacy GSC–derived orthotopic xenograft models. Additionally, strongly correlated primary human GBM samples had prognostic value patients subgroup. Collectively, our findings unveil protein stabilization potential target GSC-directed

Язык: Английский

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Nitric oxide prevents aortic valve calcification by S-nitrosylation of USP9X to activate NOTCH signaling

Science Advances, Год журнала: 2021, Номер 7(6)

Опубликована: Фев. 5, 2021

The protective role of nitric oxide in calcific aortic valve disease is mediated by S-nitrosylation proteins.

Язык: Английский

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