USP22‐mediated deubiquitination of PTEN inhibits pancreatic cancer progression by inducing p21 expression

Ren, Dianyun; Sun, Yan; Li, Dan; Wu, Heshui; Jin, Xin

doi:10.1002/1878-0261.13137

Cited by 16 publications

(14 citation statements)

References 48 publications

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“…In addition, we found an E2410* nonsense mutation (prematurely terminated protein) of the Ankyrin repeat and KH domain-containing protein 1 (ANKHD1, UniprotID: Q8IWZ3) in PDAC, which native form has been suggested to be involved in cell proliferation of various cancers (Almeida & Machado-Neto, 2020; Fragiadaki & Zeidler, 2018). Furthermore, ANKHD1 has been described to inhibit Cyclin-dependent kinase inhibitor 1 (CDKN1A) expression in pancreatic cancer and is even suggested as potential therapeutic target (Ren, Sun, Li, Wu, & Jin, 2022). However, to evaluate the influence of the here observed SAAV, further investigations are required which is beyond the scope of this project.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, ANKHD1 has been described to inhibit Cyclin-dependent kinase inhibitor 1 (CDKN1A) expression in pancreatic cancer and is even suggested as potential therapeutic target (Ren, Sun, Li, Wu, & Jin, 2022). However, to evaluate the influence of the here observed SAAV, further investigations are required which is beyond the scope of this project.…”

Section: Proteogenomic Analysis and Identification Of Single Amino Ac...mentioning

confidence: 99%

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Targeted and Explorative Profiling of Kallikrein Proteases and Global Proteome Biology of Pancreatic Ductal Adenocarcinoma, Chronic Pancreatitis, and Normal Pancreas Highlights Disease-Specific Proteome Remodelling

Werner

Bernhard

Cosenza-Contreras

et al. 2022

Preprint

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Pancreatic ductal adenocarcinoma (PDAC) represents one of the most aggressive and lethal malignancies worldwide with an urgent need for new diagnostic and therapeutic strategies. One major risk factor for PDAC is the pre-indication of chronic pancreatitis (CP), which represents highly inflammatory pancreatic tissue. Kallikreins (KLKs) are secreted serine proteases that play an important role in various cancers as components of the tumor microenvironment. Previous studies of KLKs in solid tumors largely relied on either transcriptomics or immunodetection. We present one of the first targeted mass spectrometry profiling of kallikrein proteases in PDAC, CP, and normal pancreas. We show that KLK6 and KLK10 are significantly upregulated in PDAC (n=14) but not in CP (n=7) when compared to normal pancreas (n=21), highlighting their specific intertwining with malignancy. Additional explorative proteome profiling identified 5936 proteins in our pancreatic cohort and observed disease-specific proteome rearrangements in PDAC and CP. As such, PDAC features an enriched proteome motif for extracellular matrix (ECM) and cell adhesion while there is depletion of mitochondrial energy metabolism proteins, reminiscent of the Warburg effect. Although often regarded as a PDAC hallmark, the ECM fingerprint was also observed in CP, alongside with a prototypical inflammatory proteome motif as well as with an increased wound healing process and proteolytic activity, thereby possibly illustrating tissue autolysis. Proteogenomic analysis based on publicly accessible data sources identified 112 PDAC-specific and 32 CP-specific single amino acid variants, which among others affect KRAS and ANKHD1. Our study emphasizes the diagnostic potential of kallikreins and provides novel insights into proteomic characteristics of PDAC and CP.

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Section: Resultsmentioning

confidence: 99%

Section: Proteogenomic Analysis and Identification Of Single Amino Ac...mentioning

confidence: 99%

Targeted and Explorative Profiling of Kallikrein Proteases and Global Proteome Biology of Pancreatic Ductal Adenocarcinoma, Chronic Pancreatitis, and Normal Pancreas Highlights Disease-Specific Proteome Remodelling

Werner

Bernhard

Cosenza-Contreras

et al. 2022

Preprint

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“…It will be interesting to evaluate the possible crosstalk between deubiquitination and other posttranslational modifications, such as acetylation 115 , methylation 116 , and SUMO ylation 11 , during the control of PTEN stability and activity. Given recent discoveries revealing that distinct PTEN isoforms and active PTEN dimers are related to specific PTEN functions 3 , it will be interesting to determine whether and how the aforementioned and several other PTEN DUBs 117 – 119 impact the stability, localization and biological activity of dimeric PTEN and various PTEN isoforms. PTEN is a major tumor suppressor protein whose expression and activity often serve as the bases of diagnostic and prognostic assessment; however, no available therapy that directly targets PTEN itself is currently available.…”

Section: Discussionmentioning

confidence: 99%

The equilibrium of tumor suppression: DUBs as active regulators of PTEN

et al. 2022

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PTEN is among the most commonly lost or mutated tumor suppressor genes in human cancer. PTEN, a bona fide lipid phosphatase that antagonizes the highly oncogenic PI3K-AKT-mTOR pathway, is considered a major dose-dependent tumor suppressor. Although PTEN function can be compromised by genetic mutations in inherited syndromes and cancers, posttranslational modifications of PTEN may also play key roles in the dynamic regulation of its function. Notably, deregulated ubiquitination and deubiquitination lead to detrimental impacts on PTEN levels and subcellular partitioning, promoting tumorigenesis. While PTEN can be targeted by HECT-type E3 ubiquitin ligases for nuclear import and proteasomal degradation, studies have shown that several deubiquitinating enzymes, including HAUSP/USP7, USP10, USP11, USP13, OTUD3 and Ataxin-3, can remove ubiquitin from ubiquitinated PTEN in cancer-specific contexts and thus reverse ubiquitination-mediated PTEN regulation. Researchers continue to reveal the precise molecular mechanisms by which cancer-specific deubiquitinases of PTEN regulate its roles in the pathobiology of cancer, and new methods of pharmacologically for modulating PTEN deubiquitinases are critical areas of investigation for cancer treatment and prevention. Here, we assess the mechanisms and functions of deubiquitination as a recently appreciated mode of PTEN regulation and review the link between deubiquitinases and PTEN reactivation and its implications for therapeutic strategies.

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“…USP28 promotes cancer cell growth by promoting cell cycle progression and inhibiting apoptosis via FOXM1-mediated Wnt/β-catenin signaling [ 163 ], whereas USP16 regulates chromosomal condensation and G2/M progression by deubiquitinating histone H2A and polo-like kinase 1 [ 164 , 165 ]. In addition, USP22 was shown to induce cell cycle protein-dependent kinase inhibitor 1A (CDKN1A) in pancreatic cancer, and MDM2 inhibitors enhanced the anti-pancreatic cancer effect of USP22 overexpression [ 166 ].…”

Section: Pancreatic Cancermentioning

confidence: 99%

Deubiquitinases in Cancers: Aspects of Proliferation, Metastasis, and Apoptosis

Liu

LEUNG

Liang

et al. 2022

Cancers

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Deubiquitinases (DUBs) deconjugate ubiquitin (UBQ) from ubiquitylated substrates to regulate its activity and stability. They are involved in several cellular functions. In addition to the general biological regulation of normal cells, studies have demonstrated their critical roles in various cancers. In this review, we evaluated and grouped the biological roles of DUBs, including proliferation, metastasis, and apoptosis, in the most common cancers in the world (liver, breast, prostate, colorectal, pancreatic, and lung cancers). The current findings in these cancers are summarized, and the relevant mechanisms and relationship between DUBs and cancers are discussed. In addition to highlighting the importance of DUBs in cancer biology, this study also provides updated information on the roles of DUBs in different types of cancers.

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USP22‐mediated deubiquitination of PTEN inhibits pancreatic cancer progression by inducing p21 expression

Cited by 16 publications

References 48 publications

Targeted and Explorative Profiling of Kallikrein Proteases and Global Proteome Biology of Pancreatic Ductal Adenocarcinoma, Chronic Pancreatitis, and Normal Pancreas Highlights Disease-Specific Proteome Remodelling

Targeted and Explorative Profiling of Kallikrein Proteases and Global Proteome Biology of Pancreatic Ductal Adenocarcinoma, Chronic Pancreatitis, and Normal Pancreas Highlights Disease-Specific Proteome Remodelling

The equilibrium of tumor suppression: DUBs as active regulators of PTEN

Deubiquitinases in Cancers: Aspects of Proliferation, Metastasis, and Apoptosis

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