The emerging role of deubiquitinating enzymes in genomic integrity, diseases, and therapeutics

He, Meiling; Zhou, Zhuan; Shah, Anil A.; Zou, Haojing; Jin, Tao; Chen, Qianming; Wan, Yong

doi:10.1186/s13578-016-0127-1

Cited by 78 publications

(61 citation statements)

References 156 publications

(157 reference statements)

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“…Its efficacy was documented for a mouse xenograft model of myeloma and B-cell leukemia 64 . In Table 3, we list some major USP inhibitors [68][69][70][71][72][73] . However, despite the advances in DUB-targeting drug discovery, the identified compounds are still in the early stage awaiting clinical approvals.…”

Section: Pharmacological Studies For Dubsmentioning

confidence: 99%

Targeting deubiquitinase USP28 for cancer therapy

et al. 2018

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As one of the most important post-translational modifications, ubiquitination plays versatile roles in cancer-related pathways, and is involved in protein metabolism, cell-cycle progression, apoptosis, and transcription. Counteracting the activities of the E3 ligases, the deubiquitylating enzymes have been suggested as another important mechanism to modulate the ubiquitination process, and are implicated in cancer as well. In this article, we review the emerging roles of USP28 in cancer pathways as revealed by recent studies. We discuss the major mechanisms by which USP28 is involved in the cancer-related pathways, whereby USP28 regulates physiological homeostasis of ubiquitination process, DNA-damage response, and cell cycle during genotoxic stress. We further review the studies where USP28 was targeted for treating multiples cancers including non-small cell lung cancer, breast cancer, intestinal cancers, gliomas, and bladder cancer. As a result, the clinical significance of targeting USP28 for cancer therapy merits further exploration and demonstration.

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Section: Pharmacological Studies For Dubsmentioning

confidence: 99%

Targeting deubiquitinase USP28 for cancer therapy

et al. 2018

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“…The protein turnover and stability in eukaryotic cells is maintained by the ubiquitination/deubiquitination cascade (49). Our recent study found that aberrantly high levels of USP14 in the liver of obese mice and humans promote hepatosteatosis and hypertriglyceridemia by stabilizing fatty acid synthase (FASN) (32), which might increase the risk of glucose intolerance and T2DM (50).…”

Section: Discussionmentioning

confidence: 99%

Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14

Liu

Zhang

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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Endoplasmic reticulum (ER) stress plays an important role in metabolic diseases like obesity and type 2 diabetes mellitus (T2DM), although the underlying mechanisms and regulatory pathways remain to be elucidated. Here, we induced chronic low-grade ER stress in lean mice to levels similar to those in high-fat diet (HFD)–fed obese mice and found that it promoted hyperglycemia due to enhanced hepatic gluconeogenesis. Mechanistically, sustained ER stress up-regulated the deubiquitinating enzyme ubiquitin-specific peptidase 14 (USP14), which increased the stability and levels of 3′,5′-cyclic monophosphate–responsive element binding (CREB) protein (CBP) to enhance glucagon action and hepatic gluconeogenesis. Exogenous overexpression of USP14 in the liver significantly increased hepatic glucose output. Consistent with this, liver-specific knockdown of USP14 abrogated the effects of ER stress on glucose metabolism, and also improved hyperglycemia and glucose intolerance in obese mice. In conclusion, our findings show a mechanism underlying ER stress-induced disruption of glucose homeostasis, and present USP14 as a potential therapeutic target against T2DM.

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“…It has been demonstrated that ubiquitination is a reversible process that is counteracted by deubiquitinating enzymes (DUBs). DUBs recognize specific sequences of ubiquitin, its substrates or the proteasome, and primarily remove ubiquitin from the target proteins to recycle the ubiquitin, to inhibit and proofread ubiquitination, or to alter the activity state of proteins (104). Based on their Ub-protease domains, DUBs are divided into five subclasses consisting of ubiquitin C-terminal hydrolases, ubiquitin-specific proteases (USPs), ovarian tumor-related proteases, JAB1/PAB1/MPN-domain-containing metallo-enzymes, and Machado-Joseph disease protein domain proteases (105).…”

Section: Overview Of Ubiquitination and Deubiquitinationmentioning

confidence: 99%

Ubiquitination‑deubiquitination in the Hippo signaling pathway (Review)

Liu

Deng

2019

Oncol Rep

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The Hippo signaling pathway is considered to be a tissue growth regulator and tumor suppressor pathway that controls cell proliferation, differentiation, survival, regeneration and tissue homeostasis. Defects in Hippo kinases and hyperactivation of transcriptional co-activator with PDZ-binding motif and Yes-associated protein (YAP) may contribute to the development of different types of cancer. The Hippo pathway is regulated in a variety of way, of which ubiquitination is of considerable importance. Ubiquitination is a crucial post-translational protein modification in cancer cells and is an applicable target for pharmacological intervention.Ubiquitin modifications are involved in regulating various physiological processes and are counteracted by deubiquitination. Imbalanced ubiquitination-deubiquitination is closely associated with tumor initiation and progression. Therefore, the examination of the specific association between the Hippo pathway and ubiquitination is of interest. The present study reviews the modulatory mechanism of ubiquitination-deubiquitination in the Hippo signaling pathway, the recent progress in identifying therapeutic targets and strategies, and the future directions in the field that may contribute to better tumor diagnosis and treatment.

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The emerging role of deubiquitinating enzymes in genomic integrity, diseases, and therapeutics

Cited by 78 publications

References 156 publications

Targeting deubiquitinase USP28 for cancer therapy

Targeting deubiquitinase USP28 for cancer therapy

Sustained ER stress promotes hyperglycemia by increasing glucagon action through the deubiquitinating enzyme USP14

Ubiquitination‑deubiquitination in the Hippo signaling pathway (Review)

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