Over-Expression of Deubiquitinating Enzyme USP14 in  Lung Adenocarcinoma Promotes Proliferation through the  Accumulation of β-Catenin

Wu, Ning; Li, Cong; Bai, Chong; Han, Yongtao; Cho, William C.S.; Li, Qiang

doi:10.3390/ijms140610749

Cited by 94 publications

(84 citation statements)

References 41 publications

(43 reference statements)

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“…␤-Catenin, the key effector of the pathway, has been found to be targeted by multiple E3 ligases that are regulated by distinct stimuli in different contexts (12)(13)(14)(15)(16)(17). The roles of deubiquitinating enzymes in controlling the Wnt/␤-catenin pathway have also been exemplified in several studies, wherein they target either ␤-catenin, APC, or axin (20,21,37). Our present study extends these findings by defining for the first time the RING finger ubiquitin E3 ligase RNF220 as a ␤-catenin stabilizer through USP7-mediated deubiquitination, thereby suggesting a previously unknown broader role of ubiquitin E3 ligases.…”

Section: Discussionmentioning

confidence: 99%

“…Although the deubiquitinase FAM (USP9X) is able to target and stabilize ␤-catenin, it has been suggested to be mainly involved in the trafficking of ␤-catenin and E-cadherin in epithelia (19). USP14 was also found to be overexpressed in lung adenocarcinoma and able to stabilize ␤-catenin; however, it was shown to work by directly targeting the upstream regulator Dishevelled (Dvl) (20,21).…”

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confidence: 99%

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The Ubiquitin Ligase RNF220 Enhances Canonical Wnt Signaling through USP7-Mediated Deubiquitination of β-Catenin

Yang

Kong

et al. 2014

Molecular and Cellular Biology

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Wnt/␤-catenin signaling plays critical roles in embryonic development and disease. Here, we identify RNF220, a RING domain E3 ubiquitin ligase, as a new regulator of ␤-catenin. RNF220 physically interacts with ␤-catenin, but instead of promoting its ubiquitination and proteasomal degradation, it stabilizes ␤-catenin and promotes canonical Wnt signaling. Our analysis showed that RNF220 interacts with USP7, a ubiquitin-specific peptidase, which is required for RNF220 to stabilize ␤-catenin. The RNF220/USP7 complex deubiquitinates ␤-catenin and enhances canonical Wnt signaling. Interestingly, the stability of RNF220 itself is negatively regulated by Gsk3␤, which is a key component of the ␤-catenin destruction complex and is inhibited upon Wnt stimulation. Accordingly, the RNF220/USP7 complex works as a positive feedback regulator of ␤-catenin signaling. In colon cancer cells with stimulated Wnt signaling, knockdown of RNF220 or USP7 impairs Wnt signaling and expression of Wnt target genes, suggesting a potentially novel role of RNF220 in Wnt-related tumorigenesis.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Ubiquitin Ligase RNF220 Enhances Canonical Wnt Signaling through USP7-Mediated Deubiquitination of β-Catenin

Yang

Kong

et al. 2014

Molecular and Cellular Biology

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“…Although neither USP14 nor UCHL5 appears to be essential for cell survival alone, dual knockdown using RNA interference has been shown to lead to the accumulation of polyubiquitinated substrates and loss of cell viability (Koulich et al, 2008;Tian et al, 2013;Wang et al, 2014). Interestingly several reports have shown that USP14 is consistently overexpressed in solid tumours of lung and ovarian origin and associated with metastases in colorectal carcinoma suggesting a potential role in oncogenesis (Shinji et al, 2006;Wang et al, 2015;Wu et al, 2013). Considering that USP14 and UCHL5 belong to different classes of DUBs, dual inhibition of these enzymes by small molecules would a priori be expected to be possible only in the context of broad-spectrum DUB inhibition.…”

Section: Proteasomal Dubs As Drug Targets For Cancer Therapymentioning

confidence: 99%

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Selvaraju

Mazurkiewicz

Wang

et al. 2015

Drug Resistance Updates

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The ubiquitin-proteasome system (UPS) is the primary mechanism controlling the degradation of damaged, unwanted or short-lived proteins in eukaryotic cells. In addition to protein homeostasis, the UPS has also emerged as a critical node in the regulation of signalling pathways implicated in the growth and survival of cancer cells. The absolute dependency of cancer cells on a functioning UPS has been exploited in the development of anti-cancer therapies as exemplified by development of proteasome inhibitors for the treatment of certain leukemic malignancies.Deubiquitinases (DUBs) are enzyme components of the UPS that catalyse re-editing of poly ubiquitin chains and/or removal of ubiquitin en bloc from target substrates leading to alterations in protein stability and/or downstream signalling. There is a growing recognition that targeting DUB activity may be a feasible option for the development of novel anti-cancer therapies. In particular inhibition of proteasomal cysteine DUBs (i.e. USP14 and UCHL5) has been shown to be particularly cytotoxic to cancer cells leading to the accumulation of ubiquitinated proteins and proteotoxic stress. In this review we focus on the mechanisms of action of proteasome DUB inhibitors as well as the potential of such compounds to circumvent acquired drug resistance in cancer patients.

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“…IU1 treatment enhanced proteasome efficiency in vitro, with resultant degradation of the tau protein in initial studies. The clinical utility of a specific USP14 inhibitor may merit more attention, as new studies indicate that USP14 activity is necessary for WNT/ β-catenin signaling that is active in some cancers, and that high levels of USP14 correlate with gastrointestinal cancer severity and lung cancer mortality (54,55). To this end, bAP-15 is a recently developed compound that antagonizes USP14 and another proteasome-associated DUB, USP5, and displays antiproliferative activity in vitro and tumoricidal activity in animal models (56).…”

Section: Therapeuticsmentioning

confidence: 99%

Emerging therapies targeting the ubiquitin proteasome system in cancer

Weathington¹,

Mallampalli²

2014

J. Clin. Invest.

110

100

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The ubiquitin proteasome system (UPS) is an essential metabolic constituent of cellular physiology that tightly regulates cellular protein concentrations with specificity and precision to optimize cellular function. Inhibition of the proteasome has proven very effective in the treatment of multiple myeloma, and this approach is being tested for utility in other malignancies. New pharmaceuticals targeting the proteasome itself or specific proximal pathways of the UPS are in development as antiproliferatives or immunomodulatory agents. In this article, we discuss the biology of UPS-targeting drugs, their use as therapy for neoplasia, and the state of clinical and preclinical development for emerging therapeutics. IntroductionA new era in myeloma therapy. At the turn of the millennium, targeted molecular therapeutics against hematologic malignancies initiated a shift in our perspective on treatment, prognosis, and survival for patients with some of the most aggressive and fatal neoplasms. Bortezomib (branded and marketed as Velcade by Millennium Pharmaceuticals) entered the armamentarium of new antiproliferative therapies with approval in May 2003 for the hematologic malignancy multiple myeloma (MM), in which B cellderived plasma cells clonally proliferate and produce large quantities of monoclonal antibody. MM can be a devastating disease, with renal failure, blood hyperviscosity, and bone marrow invasion seen clinically. Before 2000, there were few life-prolonging therapies for the disease. Bortezomib blocks the proteolytic activity of the 26S proteasome, a cellular structure whose role in cell metabolism has now been meticulously characterized; indeed, bortezomib is the first agent available for use in humans that inhibits the activity of this system. Bortezomib quickly proved effective in refractory MM (1), and its inclusion in initial MM treatment was superior to the conventional cytotoxic chemotherapy regimen alone (2).During this time thalidomide, an agent that produced deformities in infants of mothers prescribed the drug during pregnancy, further suppressed myeloma plasma cell proliferation when added to the regimen. A decade of careful clinical trials since these first breakthrough observations has revealed that therapeutic combinations including bortezomib with thalidomide or related compounds (collectively called immunomodulatory drugs, or IMiDs) and steroids confer a very favorable prognosis compared with historic therapy, greatly prolonging the median survival time from diagnosis over this period (3). When this therapy is implemented in conjunction with autologous bone marrow stem cell transplant, recent clinical trials show a three-year progression-free survival of 60% and overall survival of 90% for patients eligible for stem cell transplant (4), compared with only 48% three-year relative survival for patients diagnosed in 1999 (5). Multiple clinical trials for this new generation of MM molecular therapies are underway, with median survival projected by some to exceed 10 years in the post-bortezomib...

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Over-Expression of Deubiquitinating Enzyme USP14 in Lung Adenocarcinoma Promotes Proliferation through the Accumulation of β-Catenin

Cited by 94 publications

References 41 publications

The Ubiquitin Ligase RNF220 Enhances Canonical Wnt Signaling through USP7-Mediated Deubiquitination of β-Catenin

The Ubiquitin Ligase RNF220 Enhances Canonical Wnt Signaling through USP7-Mediated Deubiquitination of β-Catenin

Inhibition of proteasome deubiquitinase activity: a strategy to overcome resistance to conventional proteasome inhibitors?

Emerging therapies targeting the ubiquitin proteasome system in cancer

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