Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Blood Malignancies

Gutierrez-Diaz, Blanca T.; Gu, Wei; Ntziachristos, Panagiotis

doi:10.1016/j.it.2020.02.004

Cited by 18 publications

(14 citation statements)

References 120 publications

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“…To meet this challenge, we sought to profile the selective USP7 inhibitor FT671 30 with our DIA workflow in a series of time-course experiments. The deubiquitinase USP7 is a potential anticancer drug target that is of particular interest for the treatment of hematological malignancies 12 , 13 , 31 . For example, USP7 deubiquitinates and stabilizes the E3 ligase Mdm2.…”

Section: Resultsmentioning

confidence: 99%

“…By introducing a sodium deoxycholate (SDC)-based lysis protocol, and exploiting data-independent acquisition mass spectrometry (DIA-MS) coupled to deep neural network-based data processing, we boost reproducibility, identification numbers, and quantitative accuracy. We demonstrate the power of our method by comprehensively mapping substrates of the deubiquitinase USP7, an actively investigated anticancer drug target shown to regulate the tumor suppressor p53 12 , 13 . Following inhibition with selective inhibitors, we profile the dynamics of both the proteome and the ubiquitinome at high temporal resolution.…”

Section: Introductionmentioning

confidence: 99%

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Time-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale

et al. 2021

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Mass spectrometry (MS)-based ubiquitinomics provides system-level understanding of ubiquitin signaling. Here we present a scalable workflow for deep and precise in vivo ubiquitinome profiling, coupling an improved sample preparation protocol with data-independent acquisition (DIA)-MS and neural network-based data processing specifically optimized for ubiquitinomics. Compared to data-dependent acquisition (DDA), our method more than triples identification numbers to 70,000 ubiquitinated peptides in single MS runs, while significantly improving robustness and quantification precision. Upon inhibition of the oncology target USP7, we simultaneously record ubiquitination and consequent changes in abundance of more than 8,000 proteins at high temporal resolution. While ubiquitination of hundreds of proteins increases within minutes of USP7 inhibition, we find that only a small fraction of those are ever degraded, thereby dissecting the scope of USP7 action. Our method enables rapid mode-of-action profiling of candidate drugs targeting DUBs or ubiquitin ligases at high precision and throughput.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Time-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale

et al. 2021

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“…DUBs regulate the metabolic level of substrate proteins by cleaving monoubiquitin or polyubiquitin molecules from them, thereby regulating a variety of cellular activities, including gene transcription, cell cycle, DNA repair damage, tumorigenesis, and the inflammatory immune response 20 - 23 . Inhibitors of the DUB proteins USP1, USP4, USP7, USP14, and USP33 have shown therapeutic effects in prostate cancer, lung cancer, breast cancer, and blood malignancies 24 - 28 . In addition, USP4, USP7, USP13, and USP19 have been reported to stabilize the anti-inflammatory receptor or the release of anti-inflammatory cytokines 27 , 29 , 30 .…”

Section: Introductionmentioning

confidence: 99%

USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer

et al. 2020

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Background: Tumor associated macrophages (TAMs) have strong plasticity and if reprogrammed, can clear tumor cells and regulate the adaptive immune system for cancer immunotherapy. Deubiquitinating enzymes (DUBs), which can remove ubiquitin (Ub) from Ub-modified substrates, have been associated with oncogenic metabolism but are not well-known for regulating TAMs repolarization. Methods: The expression of DUB related genes in macrophages (MΦs) was detected by reverse transcription-PCR. Flow cytometry and immunofluorescence were used to detect the changes of immune cells in the tumor microenvironment and spleen, including M1 (CD11b + F4/80 + CD86 + CD206 - ), and M2 (CD11b + F4/80 + CD86 - CD206 + ) MΦs, and IFN-γ + CD8 + T cells. A proliferation assay was used to determine the effect of M2 MΦs treated with a USP7 inhibitor on T cell proliferation. Western blotting was used to detect the expression of USP7 and the activation of the MAPK pathway. The TGCA database was used to assess the role of USP7 in the immune microenvironment of human lung adenocarcinoma (LUAD). Results: 51 DUB genes were screened and USP7 was identified as a highly expressed gene in M2 but not M1 MΦs. Specific silencing of USP7 using siRNA or USP7 inhibitors led to phenotypical and functional changes in M2 MΦs, favoring CD8 + T cells proliferation in vitro . USP7 inhibitors delayed tumor growth in mice with Lewis lung carcinoma, and promoted tumor infiltration of M1 MΦs and IFN-γ + CD8 + T cells. Depletion of TAMs attenuated these therapeutic effects. USP7 inhibition was shown to mediate MΦs reprogramming by activating the p38 MAPK pathway. Administration of USP7 inhibitors increased the expression of programmed cell death ligand 1 (PD-L1) in tumors, while blocking programmed cell death protein 1 (PD-1) provided an effective anti-tumor response. Clinical databases suggest that high expression of USP7 in LUAD was negatively correlated with innate and adaptive immunity. Conclusions: Taken together, these results provide evidence to suggest that therapeutic approaches targeting USP7, in combination with immunotherapy, should be considered for lung cancer treatment.

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“…Research on DUBs that can regulate CSCs and ITAIMs has great potential for the use of synergistic immunotherapy. The therapeutic effects of DUB inhibitors such as USP1, USP4, USP7, USP14 and USP33 have been confirmed in prostate cancer, lung cancer, breast cancer and hematological malignancies (Ma et al, 2019;Xia et al, 2019a;Guo et al, 2020;Gutierrez-Diaz et al, 2020;Lai et al, 2020).…”

Section: Dubs Involved In Stem Cell Factors Srss and Itaimmentioning

confidence: 97%

Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential

Guo

Xia

Deng

et al. 2021

Front. Cell Dev. Biol.

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Cancer stem cells (CSCs) are sparks for igniting tumor recurrence and the instigators of low response to immunotherapy and drug resistance. As one of the important components of tumor microenvironment, the tumor associated immune microenvironment (TAIM) is driving force for the heterogeneity, plasticity and evolution of CSCs. CSCs create the inhibitory TAIM (ITAIM) mainly through four stemness-related signals (SRSs), including Notch-nuclear factor-κB axis, Hedgehog, Wnt and signal transducer and activator of transcription. Ubiquitination and deubiquitination in proteins related to the specific stemness of the CSCs have a profound impact on the regulation of ITAIM. In regulating the balance between ubiquitination and deubiquitination, it is crucial for deubiquitinating enzymes (DUBs) to cleave ubiquitin chains from substrates. Ubiquitin-specific peptidases (USPs) comprise the largest family of DUBs. Growing evidence suggests that they play novel functions in contribution of ITAIM, including regulating tumor immunogenicity, activating stem cell factors, upregulating the SRSs, stabilizing anti-inflammatory receptors, and regulating anti-inflammatory cytokines. These overactive or abnormal signaling may dampen antitumor immune responses. The inhibition of USPs could play a regulatory role in SRSs and reversing ITAIM, and also have great potential in improving immune killing ability against tumor cells, including CSCs. In this review, we focus on the USPs involved in CSCs signaling pathways and regulating ITAIM, which are promising therapeutic targets in antitumor therapy.

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Deubiquitinases: Pro-oncogenic Activity and Therapeutic Targeting in Blood Malignancies

Cited by 18 publications

References 120 publications

Time-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale

Time-resolved in vivo ubiquitinome profiling by DIA-MS reveals USP7 targets on a proteome-wide scale

USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer

Deubiquitinating Enzymes Orchestrate the Cancer Stem Cell-Immunosuppressive Niche Dialogue: New Perspectives and Therapeutic Potential

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