USP29 coordinates MYC and HIF1α stabilization to promote tumor metabolism and progression

Tu, Rongfu; Kang, Wenqian; Yang, Mengjie; Wang, Liyuan; Bao, Qing; Chen, Zhi; Dong, Yan; Wang, Jingchao; Jiang, Jue; Liu, Hudan; Qing, Guoliang

doi:10.1038/s41388-021-02031-w

Cited by 27 publications

(41 citation statements)

References 50 publications

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“…Multiple components of the UPS have been proposed to regulate MYC ubiquitination and stability including both E3 Ub ligases (FBXL14, 43 UBR5, 42,44 FBW7 45 ) and DUBs (USP13, 43 USP29, 46 OTUB1 47 ). Here, we applied IMP-2373 to test the hypothesis that MYC deregulation drives dynamic changes in DUB activity as part of the adaptation of cancer cells to increased protein synthesis, employing a human lymphoblastoid B cell line, P493-6, in which conditional MYC expression is under the control of an inducible promoter.…”

Section: Resultsmentioning

confidence: 99%

Electrophile scanning by chemical proteomics reveals a potent pan-active DUB probe for investigation of deubiquitinase activity in live cells

Conole

Cao

Ende

et al. 2022

Preprint

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Deubiquitinases (DUBs) are proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates, which can lead to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB activity has been implicated in many disease states, including cancer, neurodegeneration and inflammation, making them potentially attractive targets for therapeutic intervention. The >100 known DUB enzymes have been classified primarily by their con-served active sites, but we are still building our understanding of their substrate profiles, localization and regulation of DUB activity in diverse contexts. Ubiquitin-derived covalent activity-based probes (ABPs) are the premier tool for DUB activity profiling, but their large recognition element impedes cellular permeability and presents an unmet need for small molecule ABPs which account for local DUB concentration, protein interactions, complexes, and organelle compartmentalization in intact cells or organisms. Here, through comprehensive warhead profiling we identify cyanopyrrolidine (CNPy) probe IMP-2373 (12), a small molecule pan-DUB ABP to monitor DUB activity in physiologically relevant live cell systems. Through chemical proteomics and targeted assays we demonstrate that IMP-2373 quantitatively engages more than 35 DUBs in live cells across a range of non-toxic concentrations, and in diverse cell lines and disease models, and we demonstrate its application to quantification of changes in intracellular DUB activity during MYC deregulation in a model of B cell lymphoma. IMP-2373 thus offers a complementary tool to ubiquitin ABPs to monitor dynamic DUB activity in the context of disease-relevant phenotypes.

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Section: Resultsmentioning

confidence: 99%

Electrophile scanning by chemical proteomics reveals a potent pan-active DUB probe for investigation of deubiquitinase activity in live cells

Conole

Cao

Ende

et al. 2022

Preprint

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show abstract

“…Previously, USP29 was reported to regulate tumor metabolism and progression of neuroblastoma and B cell lymphoma by controlling MYC and HIF1 α ubiquitination. [ 17 ] In a cervical cancer study, the overexpression of USP29 enables the stabilization of the cell division cycle 25A (Cdc25A) and enhances the oncogenic potential of HeLa cells. [ 18 ] In addition, USP29 was reported to promote gastric cancer cell migration by cooperating with phosphatase SCP1 to stabilize Snail protein.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions

Guan

Song

et al. 2023

Advanced Science

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Triple-negative breast cancer (TNBC) is a highly lethal malignancy with limited therapy options. TWIST1, a key transcriptional factor of epithelial-mesenchymal transition (EMT), contributes to self-renewal of cancer stem-like cells (CSCs), chemo-resistance, metastasis, and TNBC-related death. However, the mechanism by which TWIST1 is deregulated in TNBC remains elusive. Here, USP29 is identified as a bona fide deubiquitinase of TWIST1. The deubiquitination of TWIST1 catalyzed by USP29 is required for its stabilization and subsequent EMT and CSC functions in TNBC, thereby conferring chemotherapeutic resistance and metastasis. Furthermore, the results unexpectedly reveal that CDK1 functions as the direct USP29 activator. Mechanistically, CDK1-mediated phosphorylation of USP29 is essential for its deubiquitinase activity toward TWIST1 and TWIST1 driven-malignant phenotypes in TNBC, which could be markedly mitigated by the genetic ablation or pharmacological inhibition of CDK1. Moreover, the histological analyses show that CDK1 and USP29 are highly upregulated in TNBC samples, which positively correlate with the expression of TWIST1. Taken together, the findings reveal a previously unrecognized tumor-promoting function and clinical significance of the CDK1-USP29 axis through stabilizing TWIST1 and provide the preclinical evidence that targeting this axis is an appealing therapeutic strategy to conquer chemo-resistance and metastasis in TNBC.

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“…[29] MYC is a multifunctional transcription factor which regulates expression of a large number of genes involved in cellular growth, proliferation and metabolism. [30] MYC deregulation can lead to dramatically altered protein synthesis by driving massive increases in gene transcription, and enhanced production of ribosomes and translation initiation factors, [32] promoting cell growth, cell cycle progression, and genome instability, ultimately leading to oncogenesis and malignant tumor growth. Aberrant MYC is an oncogenic driver in > 50 % of human cancers, and the mechanisms by which MYC-deregulated cancers cope with radically altered protein turnover may present novel therapeutic targets.…”

Section: Cnpy Abp Imp-2373 Enables Differential Dub Activity Profilin...mentioning

confidence: 99%

Discovery of a Potent Deubiquitinase (DUB) Small‐Molecule Activity‐Based Probe Enables Broad Spectrum DUB Activity Profiling in Living Cells**

Conole,

Cao,

am Ende

et al. 2023

Angew Chem Int Ed

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Deubiquitinases (DUBs) are a family of >100 proteases that hydrolyze isopeptide bonds linking ubiquitin to protein substrates. This leads to reduced substrate degradation through the ubiquitin proteasome system. Deregulation of DUB activity has been implicated in many diseases, including cancer, neurodegeneration and auto‐inflammation, and several have been recognized as attractive targets for therapeutic intervention. Ubiquitin‐derived covalent activity‐based probes (ABPs) provide a powerful tool for DUB activity profiling, but their large recognition element impedes cellular permeability and presents an unmet need for small molecule ABPs which can account for regulation of DUB activity in intact cells or organisms. Here, through comprehensive chemoproteomic warhead profiling, we identify cyanopyrrolidine (CNPy) probe IMP‐2373 (12) as a small molecule pan‐DUB ABP to monitor DUB activity in physiologically relevant live cells. Through proteomics and targeted assays, we demonstrate that IMP‐2373 quantitatively engages more than 35 DUBs across a range of non‐toxic concentrations in diverse cell lines. We further demonstrate its application to quantification of changes in intracellular DUB activity during pharmacological inhibition and during MYC deregulation in a model of B cell lymphoma. IMP‐2373 thus offers a complementary tool to ubiquitin ABPs to monitor dynamic DUB activity in the context of disease‐relevant phenotypes.

show abstract

USP29 coordinates MYC and HIF1α stabilization to promote tumor metabolism and progression

Cited by 27 publications

References 50 publications

Electrophile scanning by chemical proteomics reveals a potent pan-active DUB probe for investigation of deubiquitinase activity in live cells

Electrophile scanning by chemical proteomics reveals a potent pan-active DUB probe for investigation of deubiquitinase activity in live cells

Phosphorylation of USP29 by CDK1 Governs TWIST1 Stability and Oncogenic Functions

Discovery of a Potent Deubiquitinase (DUB) Small‐Molecule Activity‐Based Probe Enables Broad Spectrum DUB Activity Profiling in Living Cells**

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