Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

Cruz, Lucas Lopes; Soares, Paula; Correia, Marcelo

doi:10.3390/ph14090848

Cited by 51 publications

(31 citation statements)

References 207 publications

(184 reference statements)

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“…Thereby, DUBs change the “ ubiquitin code ” (number and position of attached ubiquitin molecules) that decides the fate of the tagged protein ( 45 ). Many DUBs are linked to cancer ( 34 , 35 , 46 ). For example, Usp7 is known to act as tumor-promoting in various cancer entities ( 47 – 50 ) including breast cancer ( 51 – 53 ).…”

Section: Discussionmentioning

confidence: 99%

Degradome-focused RNA interference screens to identify proteases important for breast cancer cell growth

Hölzen

Syré²,

Mitschke³

et al. 2022

Front. Oncol.

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Proteases are known to promote or impair breast cancer progression and metastasis. However, while a small number of the 588 human and 672 murine protease genes have been extensively studied, others were neglected. For an unbiased functional analysis of all genome-encoded proteases, i.e., the degradome, in breast cancer cell growth, we applied an inducible RNA interference library for protease-focused genetic screens. Importantly, these functional screens were performed in two phenotypically different murine breast cancer cell lines, including one stem cell-like cell line that showed phenotypic plasticity under changed nutrient and oxygen availability. Our unbiased genetic screens identified 252 protease genes involved in breast cancer cell growth that were further restricted to 100 hits by a selection process. Many of those hits were supported by literature, but some proteases were novel in their functional link to breast cancer. Interestingly, we discovered that the environmental conditions influence the degree of breast cancer cell dependency on certain proteases. For example, breast cancer stem cell-like cells were less susceptible to depletion of several mitochondrial proteases in hypoxic conditions. From the 100 hits, nine proteases were functionally validated in murine breast cancer cell lines using individual knockdown constructs, highlighting the high reliability of our screens. Specifically, we focused on mitochondrial processing peptidase (MPP) subunits alpha (Pmpca) and beta (Pmpcb) and discovered that MPP depletion led to a disadvantage in cell growth, which was linked to mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Degradome-focused RNA interference screens to identify proteases important for breast cancer cell growth

Hölzen

Syré²,

Mitschke³

et al. 2022

Front. Oncol.

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“…Ubiquitination and deubiquitination are common types of PTMs involving several different cellular processes, such as signal transduction, stress response, DNA repair, and apoptosis, thus, the disorder of these PTMs is involved in the occurrence and progression of cancer (22)(23)(24)(25)(26). Ubiquitination is the covalent binding of the polypeptide ubiquitin and target protein, which is completed by three enzymes: ubiquitin activating enzyme (E1), ubiquitin-conjugating enzyme (E2) and ubiquitin ligase (E3) (25).…”

Section: Ubiquitinationmentioning

confidence: 99%

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

et al. 2022

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Bromodomain-containing protein 4 (BRD4), a member of the bromodomain and extraterminal (BET) family, is considered to be a major driver of cancer cell growth and a new target for cancer therapy. Over 30 targeted inhibitors currently in preclinical and clinical trials have significant inhibitory effects on various tumors, including acute myelogenous leukemia (AML), diffuse large B cell lymphoma, prostate cancer, breast cancer and so on. However, resistance frequently occurs, revealing the limitations of BET inhibitor (BETi) therapy and the complexity of the BRD4 expression mechanism and action pathway. Current studies believe that when the internal and external environmental conditions of cells change, tumor cells can directly modify proteins by posttranslational modifications (PTMs) without changing the original DNA sequence to change their functions, and epigenetic modifications can also be activated to form new heritable phenotypes in response to various environmental stresses. In fact, research is constantly being supplemented with regards to that the regulatory role of BRD4 in tumors is closely related to PTMs. At present, the PTMs of BRD4 mainly include ubiquitination and phosphorylation; the former mainly regulates the stability of the BRD4 protein and mediates BETi resistance, while the latter is related to the biological functions of BRD4, such as transcriptional regulation, cofactor recruitment, chromatin binding and so on. At the same time, other PTMs, such as hydroxylation, acetylation and methylation, also play various roles in BRD4 regulation. The diversity, complexity and reversibility of posttranslational modifications affect the structure, stability and biological function of the BRD4 protein and participate in the occurrence and development of tumors by regulating the expression of tumor-related genes and even become the core and undeniable mechanism. Therefore, targeting BRD4-related modification sites or enzymes may be an effective strategy for cancer prevention and treatment. This review summarizes the role of different BRD4 modification types, elucidates the pathogenesis in the corresponding cancers, provides a theoretical reference for identifying new targets and effective combination therapy strategies, and discusses the opportunities, barriers, and limitations of PTM-based therapies for future cancer treatment.

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“…The CYP2C9*2 allele has frequencies ranging from 11–13% in Middle Eastern, European, and South/Central Asian populations; however, it has an estimate of 2% in African ancestry and <1% in East Asian populations. CYP2C9*3 ranges from frequencies of around 7–11% in European populations, Middle Eastern, and South/Central Asian ancestry, but is lower in East Asian (3%) and is even lower in African populations ( Figure 4 ) [ 117 ].…”

Section: Impact Of Variability In Snp Frequency Among Ethnicitiesmentioning

confidence: 99%

Pharmacogenomics in Psychiatry Practice: The Value and the Challenges

Alchakee

Ahmed

Eldohaji

et al. 2022

IJMS

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The activity of cytochrome P450 enzymes is influenced by genetic and nongenetic factors; hence, the metabolism of exogenous psychotropic medications and potentially some endogenous neuropeptides is variably affected among different ethnic groups of psychiatric patients. The aim of this review is to highlight the most common cytochrome P450 isoenzymes associated with the metabolism of psychotropic medications (antidepressants, antipsychotics, and mood stabilizers), their variations among different populations, their impact on endogenous neurotransmitters (dopamine and serotonin), and the effect of nongenetic factors, particularly smoking, age, and pregnancy, on their metabolic activity. Furthermore, the adverse effects of psychiatric medications may be associated with certain human leukocytic antigen (HLA) genotypes. We also highlight the gene variants that may potentially increase susceptibility to obesity and metabolic syndrome, as the adverse effects of some psychiatry medications. Collectively, the literature revealed that variation of CYP450 activity is mostly investigated in relation to genetic polymorphism, and is directly correlated with individualized clinical outcomes; whereas adverse effects are associated with HLA variants, projecting the value of pharmacogenetics implementation in psychiatry clinics. Only a few previous studies have discussed the impact of such genetic variations on the metabolism of endogenous neuropeptides. In this review, we also report on the prevalence of key variants in different ethnicities, by demonstrating publicly available data from the 1000 Genomes Project and others. Finally, we highlight the future direction of further investigations to enhance the predictability of the individual gene variants to achieve precision therapies for psychiatric patients.

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Ubiquitin-Specific Proteases: Players in Cancer Cellular Processes

Cited by 51 publications

References 207 publications

Degradome-focused RNA interference screens to identify proteases important for breast cancer cell growth

Degradome-focused RNA interference screens to identify proteases important for breast cancer cell growth

Post-Translational Modifications of BRD4: Therapeutic Targets for Tumor

Pharmacogenomics in Psychiatry Practice: The Value and the Challenges

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