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1.
Mol Cell ; 83(22): 4000-4016.e6, 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37935198

RESUMO

While 19S proteasome regulatory particle (RP) inhibition is a promising new avenue for treating bortezomib-resistant myeloma, the anti-tumor impact of inhibiting 19S RP component PSMD14 could not be explained by a selective inhibition of proteasomal activity. Here, we report that PSMD14 interacts with NSD2 on chromatin, independent of 19S RP. Functionally, PSMD14 acts as a histone H2AK119 deubiquitinase, facilitating NSD2-directed H3K36 dimethylation. Integrative genomic and epigenomic analyses revealed the functional coordination of PSMD14 and NSD2 in transcriptional activation of target genes (e.g., RELA) linked to myelomagenesis. Reciprocally, RELA transactivates PSMD14, forming a PSMD14/NSD2-RELA positive feedback loop. Remarkably, PSMD14 inhibitors enhance bortezomib sensitivity and fosters anti-myeloma synergy. PSMD14 expression is elevated in myeloma and inversely correlated with overall survival. Our study uncovers an unappreciated function of PSMD14 as an epigenetic regulator and a myeloma driver, supporting the pursuit of PSMD14 as a therapeutic target to overcome the treatment limitation of myeloma.


Assuntos
Histonas , Mieloma Múltiplo , Humanos , Histonas/genética , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo , Bortezomib/farmacologia , Bortezomib/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/genética , Mieloma Múltiplo/patologia , Linhagem Celular Tumoral , Enzimas Desubiquitinantes/metabolismo , Inibidores de Proteassoma/farmacologia , Transativadores/metabolismo
2.
Front Cell Dev Biol ; 9: 686737, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34336836

RESUMO

Many carcinomas feature hypoxia, a condition has long been associated with tumor progression and poor prognosis, as well as resistance to chemoradiotherapy. Here, we report that the F-box protein JFK promotes mammary tumor initiation and progression in MMTV-PyMT murine model of spontaneous breast cancer. We find that JFK is inducible under hypoxic conditions, in which hypoxia-inducible factor HIF-1α binds to and transcriptionally activates JFK in breast cancer cells. Consistently, analysis of public clinical datasets reveals that the mRNA level of JFK is positively correlated with that of HIF-1α in breast cancer. We show that JFK deficiency leads to a decrease in HIF-1α-induced glycolysis in breast cancer and sensitizes hypoxic breast cancer cells to ionizing radiation and chemotherapeutic treatment. These results indicate that JFK is an important player in hypoxic response, supporting the pursuit of JFK as a potential therapeutic target for breast cancer intervention.

3.
Biochem Biophys Res Commun ; 574: 48-55, 2021 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-34438346

RESUMO

Survivin is the key component of the chromosomal passenger complex and plays important roles in the regulation of cell division. Survivin has also been implicated in the regulation of apoptosis and tumorigenesis. Although the survivin protein has been reported to be degraded by a ubiquitin/proteasome-dependent mechanism, whether there is a DUB that is involved in the regulation of its protein stability is largely unknown. Using an expression library containing 68 deubiquitinating enzymes, we found that ubiquitin-specific-processing protease 35 (USP35) regulates survivin protein stability in an enzymatic activity-dependent manner. USP35 interacted with and promoted the deubiquitination of the survivin protein. USP38, an ortholog of USP35 encoded by the human genome, is also able to regulate survivin protein stability. Moreover, we found that the deubiquitinating enzyme DUBAI, the Drosophila homolog of human USP35, is able to regulate the protein stability of Deterin, the Drosophila homolog of survivin. Interestingly, USP35 also regulated the protein stability of Aurora B and Borealin which are also the component of the chromosomal passenger complex. By regulating protein stabilities of chromosomal passenger complex components, USP35 regulated cancer cell proliferation. Taken together, our work uncovered an evolutionarily conserved relationship between USP35 and survivin that might play an important role in cell proliferation.


Assuntos
Endopeptidases/metabolismo , Survivina/metabolismo , Proliferação de Células , Células Cultivadas , Endopeptidases/genética , Humanos , Estabilidade Proteica , Survivina/genética
4.
Int J Biol Macromol ; 181: 1081-1091, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33864866

RESUMO

Deubiquitinating enzymes (DUBs) play important roles in many physiological and pathological processes by modulating the ubiquitination of their substrates. DUBs undergo post-translational modifications including ubiquitination. However, whether DUBs can reverse their own ubiquitination and regulate their own protein stability requires further investigation. To answer this question, we screened an expression library of DUBs and their enzymatic activity mutants and found that some DUBs regulated their own protein stability in an enzymatic activity- and homomeric interaction-dependent manner. Taking Ubiquitin-specific-processing protease 29 (USP29) as an example, we found that USP29 deubiquitinates itself and protects itself from proteasomal degradation. We also revealed that the N-terminal region of USP29 is critical for its protein stability. Taken together, our work demonstrates that at least some DUBs regulate their own ubiquitination and protein stability. Our findings provide novel molecular insight into the diverse regulation of DUBs.


Assuntos
Enzimas Desubiquitinantes/química , Proteases Específicas de Ubiquitina/química , Ubiquitina/química , Ubiquitinação/genética , Animais , Enzimas Desubiquitinantes/genética , Estabilidade Enzimática/genética , Humanos , Complexo de Endopeptidases do Proteassoma/química , Processamento de Proteína Pós-Traducional/genética
5.
Cancer Cell Int ; 19: 222, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467488

RESUMO

BACKGROUND: Myeloid cell leukaemia 1 (MCL1) is a pro-survival Bcl-2 family protein that plays important roles in cell survival, proliferation, differentiation and tumourigenesis. MCL1 is a fast-turnover protein that is degraded via an ubiquitination/proteasome-dependent mechanism. Although several E3 ligases have been discovered to promote the ubiquitination of MCL1, the deubiquitinating enzyme (DUB) that regulates its stability requires further investigation. METHODS: The immunoprecipitation was used to determine the interaction between OTUD1 and MCL1. The ubiquitination assays was performed to determine the regulation of MCL1 by OTUD1. The cell viability was used to determine the regulation of BH3-mimetic inhibitor induced cell death by OTUD1. The survival analysis was used to determine the relationship between OTUD1 expression levels and the survival rate of cancer patients. RESULTS: By screening a DUB expression library, we determined that the deubiquitinating enzyme OTUD1 regulates MCL1 protein stability in an enzymatic-activity dependent manner. OTUD1 interacts with MCL1 and promotes its deubiquitination. Knockdown of OTUD1 increases the sensitivity of tumour cells to the BH3-mimetic inhibitor ABT-263, while overexpression of OTUD1 increases tumour cell tolerance of ABT-263. Furthermore, bioinformatics analysis data reveal that OTUD1 is a negative prognostic factor for liver cancer, ovarian cancer and specific subtypes of breast and cervical cancer. CONCLUSIONS: The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein. Thus, OTUD1 could be considered as a therapeutic target for curing these cancers.

6.
Mol Cell Biol ; 38(2)2018 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-29061731

RESUMO

The c-Jun gene encodes a transcription factor that has been implicated in many physiological and pathological processes. c-Jun is a highly unstable protein that is degraded through a ubiquitination/proteasome-dependent mechanism. However, the deubiquitinating enzyme (DUB) that regulates the stability of the c-Jun protein requires further investigation. Here, by screening a DUB expression library, we identified ubiquitin-specific protease 6 (USP6) and showed that it regulates the stability of the c-Jun protein in a manner depending on its enzyme activity. USP6 interacts with c-Jun and antagonizes its ubiquitination. USP6 overexpression upregulates the activity of the downstream signaling pathway mediated by c-Jun/AP-1 and promotes cell invasion. Moreover, many aberrant genes that are upregulated in USP6 translocated nodular fasciitis are great potential targets regulated by c-Jun. Based on our data, USP6 is an enzyme that deubiquitinates c-Jun and regulates its downstream cellular functions.


Assuntos
Fasciite/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Ubiquitina Tiolesterase/metabolismo , Movimento Celular , Feminino , Regulação da Expressão Gênica , Células HeLa , Humanos , Células MCF-7 , Estabilidade Proteica , Transporte Proteico , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas c-jun/genética , Transdução de Sinais , Fator de Transcrição AP-1/metabolismo , Ubiquitina/metabolismo , Ubiquitina Tiolesterase/genética , Ubiquitinação
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