USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin

Ji, Lei; Lü, Bo; Zamponi, Raffaella; Charlat, Olga; Aversa, Robert J.; Yang, Zinger; Sigoillot, Frederic; Zhu, Xiaoping; Hu, Tiancen; Reece‐Hoyes, John S.; Russ, Carsten; Michaud, Gregory A.; Tchorz, Jan S.; Jiang, Xiaomo; Cong, Feng

doi:10.1038/s41467-019-12143-3

Cited by 90 publications

(88 citation statements)

References 60 publications

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“…We also observed an increase in p‐β‐catenin (Ser33/Ser37/Thr41) and a decrease in active β‐catenin and p‐GSK3 (phosphorylated at Ser9) levels is a response to combined treatment, especially after 48 hr, as measured by western blot analysis and densitometry (Figure c). Active β‐catenin represents the stabilized form of β‐catenin, that is not phosphorylated by GSK3β (Ji et al, ). Taken together, these results indicated that the combination of the two drugs dampened Wnt/β‐catenin signaling pathway, most likely through the activation of GSK3β and proteasomal degradation of β‐catenin.…”

Section: Resultsmentioning

confidence: 99%

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Evangelisti

Chiarini

Cappellini

et al. 2020

Journal Cellular Physiology

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T‐cell acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological disorder that results from the clonal transformation of T‐cell precursors. Phosphatidylinositol 3‐kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) and canonical Wnt/β‐catenin signaling pathways play a crucial role in T‐cell development and in self‐renewal of healthy and leukemic stem cells. Notably, β‐catenin is a transcriptional regulator of several genes involved in cancer cell proliferation and survival. In this way, aberrations of components belonging to the aforementioned networks contribute to T‐ALL pathogenesis. For this reason, inhibition of both pathways could represent an innovative strategy in this hematological malignancy. Here, we show that combined targeting of Wnt/β‐catenin pathway through ICG‐001, a CBP/β‐catenin transcription inhibitor, and of the PI3K/Akt/mTOR axis through ZSTK‐474, a PI3K inhibitor, downregulated proliferation, survival, and clonogenic activity of T‐ALL cells. ICG‐001 and ZSTK‐474 displayed cytotoxic effects, and, when combined together, induced a significant increase in apoptotic cells. This induction of apoptosis was associated with the downregulation of Wnt/β‐catenin and PI3K/Akt/mTOR pathways. All these findings were confirmed under hypoxic conditions that mimic the bone marrow niche where leukemic stem cells are believed to reside. Taken together, our findings highlight potentially promising treatment consisting of cotargeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐ALL settings.

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Section: Resultsmentioning

confidence: 99%

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Evangelisti

Chiarini

Cappellini

et al. 2020

Journal Cellular Physiology

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“…Scaffolding protein AXIN is the rate-limiting component of the β-catenin destruction complex, which are constantly surveyed and regulated by tankyrases [56][57][58]. Tankyrases belong to the Poly (ADP-ribose) polymerases (PARPs) family, regulating the stability of AXIN1 and AXIN2 through directing AXIN ubiquitylation by RNF146 and proteasomal degradation [59,60].…”

Section: Agents Targeting the β-Catenin-destruction Complex Tankyrasementioning

confidence: 99%

Targeting the Wnt/β-catenin signaling pathway in cancer

2020

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The aberrant Wnt/β-catenin signaling pathway facilitates cancer stem cell renewal, cell proliferation and differentiation, thus exerting crucial roles in tumorigenesis and therapy response. Accumulated investigations highlight the therapeutic potential of agents targeting Wnt/β-catenin signaling in cancer. Wnt ligand/ receptor interface, β-catenin destruction complex and TCF/β-catenin transcription complex are key components of the cascade and have been targeted with interventions in preclinical and clinical evaluations. This scoping review aims at outlining the latest progress on the current approaches and perspectives of Wnt/β-catenin signaling pathway targeted therapy in various cancer types. Better understanding of the updates on the inhibitors, antagonists and activators of Wnt/β-catenin pathway rationalizes innovative strategies for personalized cancer treatment. Further investigations are warranted to confirm precise and secure targeted agents and achieve optimal use with clinical benefits in malignant diseases.

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“…[313][314][315] In addition, the deubiquitinating enzymes USP34/USP7, CYLD/USP9X and USP4 can bind to Axin, Dvl and β-catenin, respectively, thereby promoting the nuclear localization of β-catenin and the Wnt signaling pathway by inhibiting their ubiquitination. [316][317][318][319][320] Ubiquitination in the Hippo-YAP signaling pathway In mammals, the Hippo signaling pathway can also maintain CSC stemness, regulate cell growth, control the size of organs and take part in tumorigenesis. 321,322 Ubiquitination also plays an important role in regulating the Hippo signaling pathway, with a variety of E3 ligases being identified.…”

Section: Nanog Ubiquitinationmentioning

confidence: 99%

The role of ubiquitination in tumorigenesis and targeted drug discovery

Deng

Meng

Chen

et al. 2020

Sig Transduct Target Ther

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308

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Ubiquitination, an important type of protein posttranslational modification (PTM), plays a crucial role in controlling substrate degradation and subsequently mediates the "quantity" and "quality" of various proteins, serving to ensure cell homeostasis and guarantee life activities. The regulation of ubiquitination is multifaceted and works not only at the transcriptional and posttranslational levels (phosphorylation, acetylation, methylation, etc.) but also at the protein level (activators or repressors). When regulatory mechanisms are aberrant, the altered biological processes may subsequently induce serious human diseases, especially various types of cancer. In tumorigenesis, the altered biological processes involve tumor metabolism, the immunological tumor microenvironment (TME), cancer stem cell (CSC) stemness and so on. With regard to tumor metabolism, the ubiquitination of some key proteins such as RagA, mTOR, PTEN, AKT, c-Myc and P53 significantly regulates the activity of the mTORC1, AMPK and PTEN-AKT signaling pathways. In addition, ubiquitination in the TLR, RLR and STING-dependent signaling pathways also modulates the TME. Moreover, the ubiquitination of core stem cell regulator triplets (Nanog, Oct4 and Sox2) and members of the Wnt and Hippo-YAP signaling pathways participates in the maintenance of CSC stemness. Based on the altered components, including the proteasome, E3 ligases, E1, E2 and deubiquitinases (DUBs), many molecular targeted drugs have been developed to combat cancer. Among them, small molecule inhibitors targeting the proteasome, such as bortezomib, carfilzomib, oprozomib and ixazomib, have achieved tangible success. In addition, MLN7243 and MLN4924 (targeting the E1 enzyme), Leucettamol A and CC0651 (targeting the E2 enzyme), nutlin and MI-219 (targeting the E3 enzyme), and compounds G5 and F6 (targeting DUB activity) have also shown potential in preclinical cancer treatment. In this review, we summarize the latest progress in understanding the substrates for ubiquitination and their special functions in tumor metabolism regulation, TME modulation and CSC stemness maintenance. Moreover, potential therapeutic targets for cancer are reviewed, as are the therapeutic effects of targeted drugs.Signal Transduction and Targeted Therapy (2020) 5:11; https://doi.

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USP7 inhibits Wnt/β-catenin signaling through promoting stabilization of Axin

Cited by 90 publications

References 60 publications

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Targeting Wnt/β‐catenin and PI3K/Akt/mTOR pathways in T‐cell acute lymphoblastic leukemia

Targeting the Wnt/β-catenin signaling pathway in cancer

The role of ubiquitination in tumorigenesis and targeted drug discovery

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