Deubiquitinases and the new therapeutic opportunities offered to cancer

Pfoh, Roland; Lacdao, Ira Kay; Saridakis, V.

doi:10.1530/erc-14-0516

Cited by 119 publications

(127 citation statements)

References 213 publications

(232 reference statements)

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“…Furthermore, increased A20 expression or activity has also been associated with dampening numerous disease outcomes (29,30). Thus, there is great interest in manipulating A20 for therapeutic benefit (31). In regard to the TLR pathways, prior studies have identified cross talk between TLR9, TLR2, and TLR4 in both periodontitis and other disease models (18,32).…”

Section: Tlr9 and A20 In Periodontal Inflammationmentioning

confidence: 99%

“…It is possible that, although it is still a functional protein in the course of periodontitis, A20 expression does not reach sufficient levels to facilitate the resolution of inflammation. Thus, the questions that remain to be answered are how A20 levels and activity are regulated and whether the manipulation of A20 can prevent further periodontal tissue destruction, similar to its effects in other inflammatory diseases (29)(30)(31).…”

Section: Tlr9 and A20 In Periodontal Inflammationmentioning

confidence: 99%

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Interplay of Toll-Like Receptor 9, Myeloid Cells, and Deubiquitinase A20 in Periodontal Inflammation

et al. 2017

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Toll-like receptor 9 (TLR9)-deficient (TLR9 Ϫ/Ϫ ) mice are resistant to periodontitis, a disease characterized by a dysbiotic microbiota and deregulated immune response and resulting in tooth loss and various systemic conditions. However, the mechanisms and biological pathways by which TLR9 instigates periodontal inflammation are yet to be identified. In a ligature-induced model of periodontitis, we demonstrate that TLR9 Ϫ/Ϫ mice exhibited significantly less alveolar bone loss than their wild-type (WT) counterparts. Consistent with the disease phenotype, gingival tissues showed significantly more inflammatory cell infiltration in the WT ligated but not in the TLR9 Ϫ/Ϫ ligated mice compared to the unligated controls. The peritoneal infection model using Porphyromonas gingivalis, a keystone pathogen for periodontitis, revealed reduced neutrophils in TLR9 Ϫ/Ϫ mice on day 1 postinfection compared to the levels in WT mice. Transcriptomics analyses showed increased expression of A20 (tumor necrosis factor alpha [TNF-␣]-induced protein 3 [TNFAIP3]), an inhibitor of the NF-B pathway and a negative regulator of TLR signaling, in ligated TLR9 Ϫ/Ϫ mouse gingival tissues compared to its expression in the WT. Ex vivo, TLR9 Ϫ/Ϫ bone marrow-derived macrophages produced more A20 than WT cells following P. gingivalis challenge. Clinically, A20 was modestly upregulated in human gingival tissue specimens from chronic periodontitis patients, further confirming the biological relevance of A20 in periodontal inflammation. We conclude that TLR9 modulates periodontal disease progression at both the cellular and molecular level and identify A20 as a novel downstream signaling molecule in the course of periodontal inflammation. Understanding the regulation of the TLR9 signaling pathway and the involvement of A20 as a limiting factor of inflammation will uncover alternative therapeutic targets to treat periodontitis and other chronic inflammatory diseases.

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Section: Tlr9 and A20 In Periodontal Inflammationmentioning

confidence: 99%

Section: Tlr9 and A20 In Periodontal Inflammationmentioning

confidence: 99%

Interplay of Toll-Like Receptor 9, Myeloid Cells, and Deubiquitinase A20 in Periodontal Inflammation

et al. 2017

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“…The pharmacological inhibition of ubiquitin-proteasome molecular targets, to modulate the stability of tumor suppressor proteins, has received increased interests [20]. Early studies on USP7 inhibition have shown antitumor properties in multiple myeloma [21], in neuroblastoma [22] and in p53 wild-type and null isogenic cancer cells [23].…”

Section: Introductionmentioning

confidence: 99%

USP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs

et al. 2017

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“…(D'Arcy et al, 2015; Pfoh et al, 2015). UPS consists of a tagging molecule–ubiquitin and a multi-subunit proteolytic complex–the 26S proteasome.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy

et al. 2018

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Dysfunction or dysregulation of the ubiquitin proteasome system (UPS) is closely related to tumorigenesis and the development of multiple cancers. Targeting the UPS provides a new anticancer therapeutic strategy, but clinically available UPS-targeted inhibitors, including lenalidomide and bortezomib, are limited to treat solid tumors. Under physiological conditions, deubiquitinases or deubiquitinating enzymes (DUBs) play vital roles in the UPS by removing ubiquitin from substrate proteins and regulating their proteasomal degradation and sub-localization, thus maintaining the balance between ubiquitination and deubiquitination for protein quality control and homeostasis. The aberrant expression or function of DUBs generally leads to the occurrence and progression of a series of disorders, including malignant tumors. Therefore, targeting DUBs is a novel anticancer therapeutic strategy. Ubiquitin-specific proteases (USPs) are the largest subfamily of DUBs which have attracted considerable interest as anticancer targets. Most of USPs are abnormally activated or expressed in a variety of malignant tumors or in the tumor microenvironment, making them ideal anticancer target candidates, which indicates that USPs inhibitors may be a class of potential anticancer therapeutic agents. However, there are no relevant inhibitors targeting USPs have entered clinical trial so far. In this review, we will summarize the roles and mechanisms of USPs in malignant transformation and progression as well as recent advances of small-molecule inhibitors targeting USPs.

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Deubiquitinases and the new therapeutic opportunities offered to cancer

Cited by 119 publications

References 213 publications

Interplay of Toll-Like Receptor 9, Myeloid Cells, and Deubiquitinase A20 in Periodontal Inflammation

Interplay of Toll-Like Receptor 9, Myeloid Cells, and Deubiquitinase A20 in Periodontal Inflammation

USP7 inhibitors, downregulating CCDC6, sensitize lung neuroendocrine cancer cells to PARP-inhibitor drugs

Inhibition of Ubiquitin-Specific Proteases as a Novel Anticancer Therapeutic Strategy

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