UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop

Zhang, Xiao Wei; Wang, Xiao Feng; Ni, Su; Qin, Wei; Zhao, Li; Hua, Rui‐Xi; Lu, Yao; Li, Jin; Dimri, Goberdhan P.; Guo, Wei

doi:10.1002/path.4478

Cited by 23 publications

(17 citation statements)

References 40 publications

(61 reference statements)

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“…Our results provide converging evidence indicating that UBTD1 is associated with the YAP degradation complex and participates in its ubiquitylation by b-TRCP. Contrary to what has been described for MDM2, it seems that UBTD1 acts mainly on b-TRCP functionality rather than E3 ligase stability [10]. Thus, we can extrapolate that MDM2 and b-TRCP are probably not the only E3 ligases regulated by UBTD1.…”

Section: Discussioncontrasting

confidence: 84%

“…Even if its biological functions remain largely unknown, UBTD1 expression is regulated by P53 and induces cellular senescence by stabilizing P53 through degradation of murine double minute 2 (MDM2). UBTD1 is down‐regulated in gastric cancer cells and tissues, and its expression correlates with patient survival suggesting that it could act as a tumor suppressor . Moreover, UBTD1 is highly expressed in cells/tissues that are subjected to constant or intermittent mechanical constraints, such as cardiac or smooth muscle cells and basal cells of the epithelium (skin, intestine, and lung) or glands (prostate and thyroid) .…”

Section: Introductionmentioning

confidence: 99%

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UBTD1 is a mechano‐regulator controlling cancer aggressiveness

et al. 2019

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Ubiquitin domain‐containing protein 1 (UBTD1) is highly evolutionary conserved and has been described to interact with E2 enzymes of the ubiquitin–proteasome system. However, its biological role and the functional significance of this interaction remain largely unknown. Here, we demonstrate that depletion of UBTD1 drastically affects the mechanical properties of epithelial cancer cells via RhoA activation and strongly promotes their aggressiveness. On a stiff matrix, UBTD1 expression is regulated by cell–cell contacts, and the protein is associated with β‐catenin at cell junctions. Yes‐associated protein (YAP) is a major cell mechano‐transducer, and we show that UBTD1 is associated with components of the YAP degradation complex. Interestingly, UBTD1 promotes the interaction of YAP with its E3 ubiquitin ligase β‐TrCP. Consequently, in cancer cells, UBTD1 depletion decreases YAP ubiquitylation and triggers robust ROCK2‐dependent YAP activation and downstream signaling. Data from lung and prostate cancer patients further corroborate the in cellulo results, confirming that low levels of UBTD1 are associated with poor patient survival, suggesting that biological functions of UBTD1 could be beneficial in limiting cancer progression.

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Section: Discussioncontrasting

confidence: 84%

Section: Introductionmentioning

confidence: 99%

UBTD1 is a mechano‐regulator controlling cancer aggressiveness

et al. 2019

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“…NKD1 is involved in Wnt signaling central to tumor cell growth in CRC and other cancers [31]. Lower expression of UBTD1 correlates with worse prognosis [32]. SERPINB3 has a driving role in more aggressive cellular phenotypes of CRC [33].…”

Section: Resultsmentioning

confidence: 99%

Development of somatic mutation signatures for risk stratification and prognosis in lung and colorectal adenocarcinomas

et al. 2019

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BackgroundPrognostic signatures are vital to precision medicine. However, development of somatic mutation prognostic signatures for cancers remains a challenge. In this study we developed a novel method for discovering somatic mutation based prognostic signatures.ResultsSomatic mutation and clinical data for lung adenocarcinoma (LUAD) and colorectal adenocarcinoma (COAD) from The Cancer Genome Atlas (TCGA) were randomly divided into training (n = 328 for LUAD and 286 for COAD) and validation (n = 167 for LUAD and 141 for COAD) datasets. A novel method of using the log2 ratio of the tumor mutation frequency to the paired normal mutation frequency is computed for each patient and missense mutation. The missense mutation ratios were mean aggregated into gene-level somatic mutation profiles. The somatic mutations were assessed using univariate Cox analysis on the LUAD and COAD training sets separately. Stepwise multivariate Cox analysis resulted in a final gene prognostic signature for LUAD and COAD. Performance was compared to gene prognostic signatures generated using the same pipeline but with different somatic mutation profile representations based on tumor mutation frequency, binary calls, and gene-gene network normalization. Signature high-risk LUAD and COAD cases had worse overall survival compared to the signature low-risk cases in the validation set (log-rank test p-value = 0.0101 for LUAD and 0.0314 for COAD) using mutation tumor frequency ratio (MFR) profiles, while all other methods, including gene-gene network normalization, have statistically insignificant stratification (log-rank test p-value ≥0.05). Most of the genes in the final gene signatures using MFR profiles are cancer-related based on network and literature analysis.ConclusionsWe demonstrated the robustness of MFR profiles and its potential to be a powerful prognostic tool in cancer. The results are robust according to validation testing and the selected genes are biologically relevant.

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“…The procedures of cellular senescence were performed as previously described according to the manufacturers' instructions ( 15 ). In brief, 48 h after transfection with C1RL-AS1-ASO, cells were washed with phosphate-buffered saline (PBS) and fixed for 15 min.…”

Section: Methodsmentioning

confidence: 99%

Silencing of LncRNA C1RL-AS1 Suppresses the Malignant Phenotype in Gastric Cancer Cells via the AKT/β-Catenin/c-Myc Pathway

Gong

Zhao

et al. 2020

Front. Oncol.

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Purpose: Numerous studies have shown that lncRNAs play vital roles in the development and progression of cancer. However, investigations of lncRNAs in gastric cancer are limited and need to be further pursued. Materials and Methods: According to RNA-seq results of gastric cancer (GC) tissues, we identified a novel lncRNA, C1RL-AS1. qRT-PCR was used to detect the expression level of C1RL-AS1 in paired GC and normal tissues. Nuclear/cytoplasmic fractionation was applied to evaluate the distribution of C1RL-AS1 in GC cells. For functional evaluation, CCK-8, colony formation, transwell, and apoptosis assays were used to determine the oncogenic role of C1RL-AS1. Results: C1RL-AS1 was upregulated in GC tissues, and high expression levels of C1RL-AS1 were associated with poor prognosis. Further in vitro functional assays revealed that silencing C1RL-AS1 attenuated the proliferation rate and migration ability and enhanced the apoptotic rate and the senescence of GC cells. The subsequent underlying mechanistic investigation revealed that Wnt/β-catenin was involved in C1RL-AS1-mediated signaling. Rescue experiments suggested that C1RL-AS1 probably promoted the malignant phenotype via the AKT/β-catenin pathway by downregulating c-Myc. Conclusions: C1RL-AS1 probably exerts its biological function by mediating the AKT/β-catenin/c-Myc pathway, indicating a novel therapeutic target in GC.

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UBTD1 induces cellular senescence through an UBTD1-Mdm2/p53 positive feedback loop

Cited by 23 publications

References 40 publications

UBTD1 is a mechano‐regulator controlling cancer aggressiveness

UBTD1 is a mechano‐regulator controlling cancer aggressiveness

Development of somatic mutation signatures for risk stratification and prognosis in lung and colorectal adenocarcinomas

Silencing of LncRNA C1RL-AS1 Suppresses the Malignant Phenotype in Gastric Cancer Cells via the AKT/β-Catenin/c-Myc Pathway

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