Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12

McClurg, Urszula L.; Chit, Nay C T H; Azizyan, Mahsa; Edwards, Joanne; Nabbi, Arash; Riabowol, Karl; Nakjang, Sirintra; McCracken, Stuart; Robson, Craig

doi:10.1038/s41388-018-0283-3

Cited by 34 publications

(31 citation statements)

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“…ARHGEF7 plays a role in cytoskeleton remodeling, and may regulate cancer cell motility [ 35 ], USF1 expression is related to cellular stress and senescence, immune response and carcinogenesis and has been shown to be associated with shorter life expectancy [ 36 ]. USP12 is a deubiquitinating enzyme that plays a critical role in TP53 tumor suppressor levels [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide DNA Methylation Profiles in Community Members Exposed to the World Trade Center Disaster

Arslan

Tuminello

Yang

et al. 2020

IJERPH

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The primary goal of this pilot study was to assess feasibility of studies among local community members to address the hypothesis that complex exposures to the World Trade Center (WTC) dust and fumes resulted in long-term epigenetic changes. We enrolled 18 WTC-exposed cancer-free women from the WTC Environmental Health Center (WTC EHC) who agreed to donate blood samples during their standard clinical visits. As a reference WTC unexposed group, we randomly selected 24 age-matched cancer-free women from an existing prospective cohort who donated blood samples before 11 September 2001. The global DNA methylation analyses were performed using Illumina Infinium MethylationEpic arrays. Statistical analyses were performed using R Bioconductor package. Functional genomic analyses were done by mapping the top 5000 differentially expressed CpG sites to the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway database. Among cancer-free subjects, we observed substantial methylation differences between WTC-exposed and unexposed women. The top 15 differentially methylated gene probes included BCAS2, OSGIN1, BMI1, EEF1A2, SPTBN5, CHD8, CDCA7L, AIDA, DDN, SNORD45C, ZFAND6, ARHGEF7, UBXN8, USF1, and USP12. Several cancer-related pathways were enriched in the WTC-exposed subjects, including endocytosis, mitogen-activated protein kinase (MAPK), viral carcinogenesis, as well as Ras-associated protein-1 (Rap1) and mammalian target of rapamycin (mTOR) signaling. The study provides preliminary data on substantial differences in DNA methylation between WTC-exposed and unexposed populations that require validation in further studies.

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Section: Discussionmentioning

confidence: 99%

Genome-Wide DNA Methylation Profiles in Community Members Exposed to the World Trade Center Disaster

Arslan

Tuminello

Yang

et al. 2020

IJERPH

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“…In PCa, fundamental components of the SE complexes, such as BDR4 and ERG, densely bind to the enhancer and SE elements to promote tumorigenesis and tumor growth. In advanced CRPC patients, the SE activity created by these transcription factors remains stable and evolves to be more specific, which makes it possible that SEs may be promising therapeutic targets 47,97,106,107 .…”

Section: Future Directionsmentioning

confidence: 99%

Super-enhancer in prostate cancer: transcriptional disorders and therapeutic targets

Chen

Shang

et al. 2020

npj Precis. Onc.

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Abnormal activity of oncogenic and tumor-suppressor signaling pathways contributes to cancer and cancer risk in humans. Transcriptional dysregulation of these pathways is commonly associated with tumorigenesis and the development of cancer. Genetic and epigenetic alterations may mediate dysregulated transcriptional activity. One of the most important epigenetic alternations is the non-coding regulatory element, which includes both enhancers and super-enhancers (SEs). SEs, characterized as large clusters of enhancers with aberrant high levels of transcription factor binding, have been considered as key drivers of gene expression in controlling and maintaining cancer cell identity. In cancer cells, oncogenes acquire SEs and the cancer phenotype relies on these abnormal transcription programs driven by SEs, which leads to cancer cells often becoming addicted to the SEs-related transcription programs, including prostate cancer. Here, we summarize recent findings of SEs and SEs-related gene regulation in prostate cancer and review the potential pharmacological inhibitors in basic research and clinical trials.

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“…USP1 can deubiquitinate and stabilize inhibitors of DNA binding proteins (IDs) and subsequently promote the maintenance of mesenchymal stem cells in osteosarcoma 6,15 . USP12 and USP46 are also involved in tumor pathogenesis by deubiquitinating and stabilizing different targets, such as PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), TP53 and androgen receptor (AR) [24][25][26][27][28] . USP12 deubiquitylates and prevents lysosomal degradation of LAT and Trat1 to maintain the proximal T-cell receptor (TCR) complex for the duration of signaling 29 .…”

mentioning

confidence: 99%

UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression

Song

Zhao

et al. 2020

Nat Commun

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NOD-like receptor protein 3 (NLRP3) detects microbial infections or endogenous danger signals and activates the NLRP3 inflammasome, which has important functions in host defense and contributes to the pathogenesis of inflammatory diseases, and thereby needs to be tightly controlled. Deubiquitination of NLRP3 is considered a key step in NLRP3 inflammasome activation. However, the mechanisms by which deubiquitination controls NLRP3 inflammasome activation are unclear. Here, we show that the UAF1/USP1 deubiquitinase complex selectively removes K48-linked polyubiquitination of NLRP3 and suppresses its ubiquitination-mediated degradation, enhancing cellular NLRP3 levels, which are indispensable for subsequent NLRP3 inflammasome assembly and activation. In addition, the UAF1/USP12 and UAF1/USP46 complexes promote NF-κB activation, enhance the transcription of NLRP3 and proinflammatory cytokines (including pro-IL-1β, TNF, and IL-6) by inhibiting ubiquitination-mediated degradation of p65. Consequently, Uaf1 deficiency attenuates NLRP3 inflammasome activation and IL-1β secretion both in vitro and in vivo. Our study reveals that the UAF1 deubiquitinase complexes enhance NLRP3 and pro-IL-1β expression by targeting NLRP3 and p65 and licensing NLRP3 inflammasome activation.

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Molecular mechanism of the TP53-MDM2-AR-AKT signalling network regulation by USP12

Cited by 34 publications

References 50 publications

Genome-Wide DNA Methylation Profiles in Community Members Exposed to the World Trade Center Disaster

Genome-Wide DNA Methylation Profiles in Community Members Exposed to the World Trade Center Disaster

Super-enhancer in prostate cancer: transcriptional disorders and therapeutic targets

UAF1 deubiquitinase complexes facilitate NLRP3 inflammasome activation by promoting NLRP3 expression

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