Divergent Modulation of Proteostasis in Prostate Cancer

Ballar, Petek; Erbaykent-Tepedelen, Burcu; Gozen, Oguz; Erzurumlu, Yalçın

doi:10.1007/978-3-030-38266-7_5

Cited by 15 publications

(12 citation statements)

References 266 publications

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“…PCa is the second most common cause of cancer death in men after lung cancer [3] and the most frequently diagnosed cancer for men in several countries such as the USA [4]. In 2018, 1,276,106 new PCa cases were diagnosed and 358,989 related deaths were recorded worldwide [5].…”

Section: Introductionmentioning

confidence: 99%

Prostate cancer management: long-term beliefs, epidemic developments in the early twenty-first century and 3PM dimensional solutions

Kučera¹,

Pecen²,

Topolčan³

et al. 2020

EPMA Journal

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In the early twenty-first century, societies around the world are facing the paradoxal epidemic development of PCa as a non-communicable disease. PCa is the most frequently diagnosed cancer for men in several countries such as the USA. Permanently improving diagnostics and treatments in the PCa management causes an impressive divergence between, on one hand, permanently increasing numbers of diagnosed PCa cases and, on the other hand, stable or even slightly decreasing mortality rates. Still, aspects listed below are waiting for innovate solutions in the context of predictive approaches, targeted prevention and personalisation of medical care (PPPM / 3PM). PCa belongs to the cancer types with the highest incidence worldwide. Corresponding economic burden is enormous. Moreover, the costs of treating PCa are currently increasing more quickly than those of any other cancer. Implementing individualised patient profiles and adapted treatment algorithms would make currently too heterogeneous landscape of PCa treatment costs more transparent providing clear “road map” for the cost saving. PCa is a systemic multi-factorial disease. Consequently, predictive diagnostics by liquid biopsy analysis is instrumental for the disease prediction, targeted prevention and curative treatments at early stages. The incidence of metastasising PCa is rapidly increasing particularly in younger populations. Exemplified by trends observed in the USA, prognosis is that the annual burden will increase by over 40% in 2025. To this end, one of the evident deficits is the reactive character of medical services currently provided to populations. Innovative screening programmes might be useful to identify persons in suboptimal health conditions before the clinical onset of metastasising PCa. Strong predisposition to systemic hypoxic conditions and ischemic lesions (e.g. characteristic for individuals with Flammer syndrome phenotype) and low-grade inflammation might be indicative for specific phenotyping and genotyping in metastasising PCa screening and disease management. Predictive liquid biopsy tests for CTC enumeration and their molecular characterisation are considered to be useful for secondary prevention of metastatic disease in PCa patients. Particular rapidly increasing PCa incidence rates are characteristic for adolescents and young adults aged 15–40 years. Patients with early onset prostate cancer pose unique challenges; multi-factorial risks for these trends are proposed. Consequently, multi-level diagnostics including phenotyping and multi-omics are considered to be the most appropriate tool for the risk assessment, prediction and prognosis. Accumulating evidence suggests that early onset prostate cancer is a distinct phenotype from both aetiological and clinical perspectives deserving particular attention from view point of 3P medical approaches.

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Section: Introductionmentioning

confidence: 99%

Prostate cancer management: long-term beliefs, epidemic developments in the early twenty-first century and 3PM dimensional solutions

Kučera¹,

Pecen²,

Topolčan³

et al. 2020

EPMA Journal

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“…Enrichment analysis also suggests a response to hypoxia and oxidative stress by HYOU1, MVP, GSTM2, quinone oxidoreductase-like protein 1, TST, BLVRB, and PRDX1 up-regulation in cells exposed to soil extracts (DxCS), as well as BLVRB related to heme degradation [56][57][58]. Interestingly, atrazine could be the cause of the observed oxidative stress [49].…”

Section: Discussionmentioning

confidence: 94%

“…The presence of pesticides was detected by GC-MS/MS analysis, though the results were below quantification limits. However, enrichment analysis also suggested the presence of the herbicide atrazine, forbidden in European countries since 1992 but probably still present in soil due to illegal disposal or past contamination being also persistent in the environment [49]. Although the soil extracts suitable for luciferase measurement in DR-CALUX ® bioassay are obtained with a mixture of highly hydrophobic and hydrophilic solvents during extraction and clean-up operations to isolate the fraction of dioxin-like chemicals, we cannot exclude that some drugs could have been retained and/or that the identified pathways obtained by the proteomics and enrichments analysis could be still activated by other dioxin-like compounds present in the extracts.…”

Section: Discussionmentioning

confidence: 99%

First Attempt to Couple Proteomics with the AhR Reporter Gene Bioassay in Soil Pollution Monitoring and Assessment

Landi

Liberatori

Cotugno

et al. 2021

Toxics

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A topsoil sample obtained from a highly industrialized area (Taranto, Italy) was tested on the DR-CALUX® cell line and the exposed cells processed with proteomic and bioinformatics analyses. The presence of polyhalogenated compounds in the topsoil extracts was confirmed by GC-MS/MS analysis. Proteomic analysis of the cells exposed to the topsoil extracts identified 43 differential proteins. Enrichment analysis highlighted biological processes, such as the cellular response to a chemical stimulus, stress, and inorganic substances; regulation of translation; regulation of apoptotic process; and the response to organonitrogen compounds in light of particular drugs and compounds, extrapolated by bioinformatics all linked to the identified protein modifications. Our results confirm and reflect the complex epidemiological situation occurring among Taranto inhabitants and underline the need to further investigate the presence and sources of inferred chemicals in soils. The combination of bioassays and proteomics reveals a more complex scenario of chemicals able to affect cellular pathways and leading to toxicities rather than those identified by only bioassays and related chemical analysis. This combined approach turns out to be a promising tool for soil risk assessment and deserves further investigation and developments for soil monitoring and risk assessment.

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“…Regulation of AR and Brg1 can be mediated through genetic or epigenetic modifications or other mechanisms, among which ubiquitination is one of the most important. Specific ubiquitin ligases, such as SPOP, Siah2, and RNF6, and deubiquitinases, such as USP14, USP26, and USP12, have been reported to be involved in the regulation of AR via the ubiquitin-proteasome system (UPS) 46 , 47 . With regard to Brg1, SCF FBW7 has been reported to be the Cullin3 ubiquitin ligase mediating the polyubiquitination and degradation of Brg1 28 , 36 .…”

Section: Discussionmentioning

confidence: 99%

OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR

Zhao

et al. 2022

Commun Biol

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Ovarian tumor (OTU) subfamily deubiquitinases are involved in various cellular processes, such as inflammation, ferroptosis and tumorigenesis; however, their pathological roles in prostate cancer (PCa) remain largely unexplored. In this study, we observed that several OTU members displayed genomic amplification in PCa, among which ovarian tumor deubiquitinase 6A (OTUD6A) amplified in the top around 15–20%. Further clinical investigation showed that the OTUD6A protein was highly expressed in prostate tumors, and increased OTUD6A expression correlated with a higher biochemical recurrence risk after prostatectomy. Biologically, wild-type but not a catalytically inactive mutant form of OTUD6A was required for PCa cell progression. In vivo experiments demonstrated that OTUD6A oligonucleotides markedly suppressed prostate tumorigenesis in PtenPC−/− mice and patient-derived xenograft (PDX) models. Mechanistically, the SWI/SNF ATPase subunit Brg1 and the nuclear receptor AR (androgen receptor) were identified as essential substrates for OTUD6A in PCa cells by a mass spectrometry (MS) screening approach. Furthermore, OTUD6A stabilized these two proteins by erasing the K27-linked polyubiquitination of Brg1 and K11-linked polyubiquitination of AR. OTUD6A amplification exhibited strong mutual exclusivity with mutations in the tumor suppressors FBXW7 and SPOP. Collectively, our results indicate the therapeutic potential of targeting OTUD6A as a deubiquitinase of Brg1 and AR for PCa treatment.

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Divergent Modulation of Proteostasis in Prostate Cancer

Cited by 15 publications

References 266 publications

Prostate cancer management: long-term beliefs, epidemic developments in the early twenty-first century and 3PM dimensional solutions

Prostate cancer management: long-term beliefs, epidemic developments in the early twenty-first century and 3PM dimensional solutions

First Attempt to Couple Proteomics with the AhR Reporter Gene Bioassay in Soil Pollution Monitoring and Assessment

OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR

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