USP21 promotes cell proliferation by maintaining the EZH2 level in diffuse large B‐cell lymphoma

Ma, Huixian; Luo, Xiangrui; Zhou, Peng; He, Na; Zhou, Jun; Liu, Min; Xie, Wei

doi:10.1002/jcla.23693

Cited by 14 publications

(11 citation statements)

References 45 publications

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“…Besides USP7, the expression of USP34 also increased in DLBCL 31 . In addition, USP21 was highly expressed in the DLBCL lymphoid tissue and it promotes DLBCL cell proliferation via stabilizing EZH2 32 . Here, we identified two novel USP7 substrates such as WDR5 and MLL2, which are the two key components of lysine‐specific methyltransferase complex.…”

Section: Discussionmentioning

confidence: 88%

“…31 In addition, USP21 was highly expressed in the DLBCL lymphoid tissue and it promotes DLBCL cell proliferation via stabilizing EZH2. 32 Here, we identified two novel USP7 substrates such as WDR5 and MLL2, which are the two key components of lysine-specific methyltransferase complex. Previous works also reported other histone methyltransferases, including MLL5 and EZH2, as well as histone demethylases such as LSD1, which are substrates of USP7 in different cancers.…”

Section: Usp7 Is Positively Correlated With Mll2 and Wdr5 As Well As ...mentioning

confidence: 98%

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USP7 sustains an active epigenetic program via stabilizing MLL2 and WDR5 in diffuse large B‐cell lymphoma

Bao

et al. 2022

Cell Biochemistry & Function

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Activated B‐cell‐like (ABC)‐diffuse large B‐cell lymphoma (ABC‐DLBCL) is a common subtype of non‐Hodgkin's lymphoma with poor prognosis. The survival of ABC‐DLBCL relies on constitutive activation of BCR signaling, but the underlying molecular mechanism is not fully addressed. By mining The Cancer Genome Atlas database, we found that the expression of ubiquitin‐specific protease 7 (USP7) is significantly elevated in three cancer types including DLBCL. Interestingly, unlike germinal center B‐cell‐like (GCB)‐DLBCL, ABC‐DLBCL shows upregulated expression of USP7. Inhibiting the enzymatic activity of USP7 (P22077) has a drastic effect on ABC‐DLBCL, but not GCB‐DLBCL cells. Compared to GCB‐DLBCL, ABC‐DLBCL cells show transcriptional upregulation of multiple components of BCR‐signaling. USP7 inhibition significantly reduces the expression of upregulated components of BCR signaling. Mechanistically, USP7 inhibition greatly reduces the methylation of histone 3 on lysine 4 (H3K4me2), which is an epigenetic marker for active enhancers. USP7 inhibition greatly reduces the protein level of WDR5 and MLL2, key components of lysine‐specific methyltransferase complex (complex of proteins associated with Set1 [COMPASS]). In ABC‐DLBCL cells, USP7 stabilizes WDR5 and MLL2. In patients, the expression of USP7 is significantly associated with components of BCR signaling (LYN, SYK, BTK, PLCG2, PRKCB, MALT1, BCL10, and CARD11) and targets of BCR signaling (MYC and IRF4). In summary, we demonstrated an essential role of USP7 in ABC‐DLBCL by organizing an oncogenic epigenetic program via stabilization of WDR5 and MLL2. Targeting USP7 might be a novel and efficient approach to treat patients with ABC‐DLBCL and it might be better than targeting individual components such as BTK in BCR signaling.

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Section: Discussionmentioning

confidence: 88%

Section: Usp7 Is Positively Correlated With Mll2 and Wdr5 As Well As ...mentioning

confidence: 98%

USP7 sustains an active epigenetic program via stabilizing MLL2 and WDR5 in diffuse large B‐cell lymphoma

Bao

et al. 2022

Cell Biochemistry & Function

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“…USP21 is overexpressed in DLBCL and promotes cell proliferation by maintaining the stability of enhancer of zeste homolog2 (EZH2), an oncogenic molecule in NHL [ 194 , 195 ]. Targeted inhibition of USP21 activity resulted in a reduction in EZH2 and thus inhibited cell growth, independent of EZH2 mutations.…”

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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“…Genome sequencing efforts have revealed somatic CYLD mutations in several human cancers, 4–8 in which it acts as a tumor suppressor through its effects on cellular proliferation, 9,10 apoptosis, 11 migration, 12 and signal transduction 13,14 . There are many kinds of deubiquitinating enzymes in mammalian cell, which play their respective functions 15–17 . The CYLD gene encodes a 956 amino acid protein with several functional domains: three N‐terminal CAP‐Gly domains and a C‐terminal ubiquitin‐specific catalytic domain 18 .…”

Section: Introductionmentioning

confidence: 99%

Potential role for the tumor suppressor CYLD in brain and notochord development

Wang

et al. 2021

Thoracic Cancer

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Background The cylindromatosis (CYLD) tumor suppressor is a microtubule‐associated deubiquitinase that plays a critical role in the regulation of cell signaling and contributes to a variety of physiological and pathological processes. However, the functions of CYLD in zebrafish are less well known, particularly with regard to their development and physiology. In this context, we investigated the loss of function of CYLD in zebrafish via transcription activator‐like effector nuclease (TALEN)‐based gene deletion. Methods Semi‐quantitative RT‐PCR was used to quantify CYLD mRNA expression in zebrafish embryos at various developmental stages. We also performed whole‐mount in situ hybridization to further assess the dynamic expression and distribution of CYLD in the entire zebrafish embryos at different stages. In addition, we deleted CYLD in zebrafish with TALENs to investigate its potential impact on embryonic development. Results The expression of CYLD mRNA varied during early embryonic development. The CYLD mRNA localized to the brain and notochord of developing zebrafish embryos. Homozygous deletion of CYLD resulted in embryonic death before 8 h post‐fertilization. Conclusions CYLD appears to play an important role in central nervous system development in zebrafish. Although severe embryonic death restricted analysis of homozygous mutants, further research into the role of CYLD in central nervous system development is warranted.

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USP21 promotes cell proliferation by maintaining the EZH2 level in diffuse large B‐cell lymphoma

Cited by 14 publications

References 45 publications

USP7 sustains an active epigenetic program via stabilizing MLL2 and WDR5 in diffuse large B‐cell lymphoma

USP7 sustains an active epigenetic program via stabilizing MLL2 and WDR5 in diffuse large B‐cell lymphoma

Deubiquitinases in hematological malignancies

Potential role for the tumor suppressor CYLD in brain and notochord development

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