Suppression of USP7 induces BCR-ABL degradation and chronic myelogenous leukemia cell apoptosis

Jiang, Shuoyi; Wang, Xiaoge; He, Yuanming; Huang, Hongbiao; Cao, Biyin; Zhang, Zubin; Liu, Jinbao; Wang, Qi; Huang, Zhongcheng; Mao, Xinliang

doi:10.1038/s41419-021-03732-6

Cited by 29 publications

(32 citation statements)

References 33 publications

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“…Recent studies have confirmed that BCR‐ABL can be degraded via the UPS, and several deubiquitinases have been reported to participate in this process. For instance, USP7 and USP25 cleave K48‐linkage poly‐ubiquitination conjugate from BCR‐ABL, which accelerates BCR‐ABL degradation through UPS 43,44 . In addition, inhibition of USP9X triggers K63‐linkage poly‐ubiquitination of BCR‐ABL, resulting in its accumulation in aggresomes 45 .…”

Section: Discussionmentioning

confidence: 99%

“…For instance, USP7 and USP25 cleave K48‐linkage poly‐ubiquitination conjugate from BCR‐ABL, which accelerates BCR‐ABL degradation through UPS. 43 , 44 In addition, inhibition of USP9X triggers K63‐linkage poly‐ubiquitination of BCR‐ABL, resulting in its accumulation in aggresomes. 45 It is still unknown whether USP14 or UCHL5 regulates the deubiquitination and subsequent degradation of BCR‐ABL protein.…”

Section: Discussionmentioning

confidence: 99%

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Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia

Jiang

Chen

et al. 2022

Clinical & Translational Med

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Background Chronic myeloid leukaemia (CML) is a haematological cancer featured by the presence of BCR‐ABL fusion protein with abnormal tyrosine kinase activation. Classical tyrosine kinase inhibitor (TKI)‐based therapies are available to patients with CML. However, acquired resistance to TKI has been a challenging obstacle, especially stubborn T315I mutation is the most common cause. Therefore, it is especially urgent to find more effective targets to overcome TKI resistance induced by BCR‐ABLT315I. Proteasomal deubiquitinases (USP14 and UCHL5) have fundamental roles in the ubiquitin‐proteasome system and possess multiple functions during cancer progression. Methods The human peripheral blood mononuclear cells were collected to measure the mRNA expression of USP14 and UCHL5, as well as to detect the toxicity effect of b‐AP15. We explored the effect of b‐AP15 on the activity of proteasomal deubiquitinases. We detected the effects of b‐AP15 on BCR‐ABLWT and BCR‐ABLT315I CML cells in vitro and in the subcutaneous tumour model. We knocked down USP14 and/or UCHL5 by shRNA to explore whether these proteasomal deubiquitinases are required for cell proliferation of CML. Results In this study, we found that increased expression of the proteasomal deubiquitinase USP14 and UCHL5 in primary cancer cells from CML patients compared to healthy donors. b‐AP15, an inhibitor of USP14 and UCHL5, exhibited potent tumour‐killing activity in BCR‐ABLWT and BCR‐ABLT315I CML cell lines, as well as in CML xenografts and primary CML cells. Mechanically, pharmacological or genetic inhibition of USP14 and UCHL5 induced cell apoptosis and decreased the protein level of BCR‐ABL in CML cells expressing BCR‐ABLWT and BCR‐ABLT315I. Moreover, b‐AP15 synergistically enhanced the cytotoxic effect caused by TKI imatinib in BCR‐ABLWT and BCR‐ABLT315I CML cells. Conclusion Collectively, our results demonstrate targeting USP14 and UCHL5 as a potential strategy for combating TKI resistance in CML.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia

Jiang

Chen

et al. 2022

Clinical & Translational Med

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“…Accumulated studies have also shown the apoptotic function of USP7 inhibition in a p53-independent manner. In chronic myelogenous leukemia (CML), USP7 is required for stabilization of BCR-ABL and activation of BCR-ABL signaling (83).Inhibiting USP7 was shown to cause BCR-ABL destabilization and to trigger apoptotic signaling pathways (83). In CLL cells, USP7 inhibition induces cell apoptosis by restoring nuclear localization of PTEN (84).…”

Section: Cell Apoptosismentioning

confidence: 99%

Ubiquitin-Specific Peptidase 7: A Novel Deubiquitinase That Regulates Protein Homeostasis and Cancers

Zhou

Ouyang

et al. 2021

Front. Oncol.

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Ubiquitin-Specific Peptidase 7 (USP7), or herpes virus-associated protease (HAUSP), is the largest family of the deubiquitinating enzymes (DUBs). Recent studies have shown that USP7 plays a vital role in regulating various physiological and pathological processes. Dysregulation of these processes mediated by USP7 may contribute to many diseases, such as cancers. Moreover, USP7 with aberrant expression levels and abnormal activity are found in cancers. Therefore, given the association between USP7 and cancers, targeting USP7 could be considered as an attractive and potential therapeutic approach in cancer treatment. This review describes the functions of USP7 and the regulatory mechanisms of its expression and activity, aiming to emphasize the necessity of research on USP7, and provide a better understanding of USP7-related biological processes and cancer.

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“…Phosphorylated USP7 gains increased deubiquitinating activity, thus promoting the nuclear exclusion of phosphatase and tensin homolog (PTEN), which disrupts PTEN’s tumor suppressive function in CML cells [ 32 , 33 ]. It is also demonstrated that USP7 interacts with BCR-ABL and blocks its polyubiquitination and degradation, thereby inhibiting its downstream signaling transduction [ 34 ]. Furthermore, USP7 is expressed mostly in the nucleus of normal CD34 + cells, but in primary CML CD34 + cells, it is expressed both in the nuclear bodies and cytoplasm [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

Deubiquitinases in hematological malignancies

Wang

et al. 2021

Biomark Res

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Deubiquitinases (DUBs) are enzymes that control the stability, interactions or localization of most cellular proteins by removing their ubiquitin modification. In recent years, some DUBs, such as USP7, USP9X and USP10, have been identified as promising therapeutic targets in hematological malignancies. Importantly, some potent inhibitors targeting the oncogenic DUBs have been developed, showing promising inhibitory efficacy in preclinical models, and some have even undergone clinical trials. Different DUBs perform distinct function in diverse hematological malignancies, such as oncogenic, tumor suppressor or context-dependent effects. Therefore, exploring the biological roles of DUBs and their downstream effectors will provide new insights and therapeutic targets for the occurrence and development of hematological malignancies. We summarize the DUBs involved in different categories of hematological malignancies including leukemia, multiple myeloma and lymphoma. We also present the recent development of DUB inhibitors and their applications in hematological malignancies. Together, we demonstrate DUBs as potential therapeutic drug targets in hematological malignancies.

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Suppression of USP7 induces BCR-ABL degradation and chronic myelogenous leukemia cell apoptosis

Cited by 29 publications

References 33 publications

Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia

Inhibition of proteasomal deubiquitinases USP14 and UCHL5 overcomes tyrosine kinase inhibitor resistance in chronic myeloid leukaemia

Ubiquitin-Specific Peptidase 7: A Novel Deubiquitinase That Regulates Protein Homeostasis and Cancers

Deubiquitinases in hematological malignancies

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