Genomic Models of Metastatic Cancer: Functional Analysis of Death-from-Cancer Signature Genes Reveals Aneuploid, Anoikis-Resistant, Metastasis-Enabling Phenotype with Altered Cell Cycle Control and Activated PcG Protein Chromatin Silencing Pathway

Glinsky, Gennadi V.

doi:10.4161/cc.5.11.2796

Cited by 154 publications

(163 citation statements)

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“…Moreover, our transcriptional profile correlate with poor prognosis features previously described for different types of malignant tumors (Glinsky, 2006) such as the increased expression of members of the inhibitor of apoptosis protein family (BIRC5), activation of mitotic spindle checkpoint proteins (BUB1, BUB3, KNTC2, MAD2 (MAD2L1), PLK4 and AURORA A (STK6)) and high levels of cell cycle control/marker proteins (CCNB2, CCNA2 and CDC2). Finally, we found that our ATC/PDTC series had a deregulation of critical genes for thyroid hormone synthesis, such as the overexpression of ARRB2 (b-arrestin 2; Voigt et al, 2000), which is implicated in the desensitization of thyroid-stimulating hormone receptors (TSHR), the underexpression of RAB5A, which participates in the thyroglobulin production (TG; Croizet-Berger et al, 2002), and a diminished expression of TG and PAX8, which has also been observed before in ATC/PDTC series (Onda et al, 2004).…”

Section: Discussionsupporting

confidence: 71%

“…We are thus in need of new approaches that may lead to improved disease management. Microarray analysis of geneexpression patterns has provided a way to identify molecular events related to specific tumor types and to specific cancer processes, such as metastasis, proliferation and angiogenesis (Glinsky, 2006). Numerous studies also have demonstrated its potential for the identification of molecular signatures associated with different clinical features (van de Vijver et al, 2002;Huang et al, 2003), that could help identify novel targets for therapy.…”

Section: Introductionmentioning

confidence: 99%

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Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information

et al. 2007

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Undifferentiated and poorly differentiated thyroid tumors are responsible for more than half of thyroid cancer patient deaths in spite of their low incidence. Conventional treatments do not obtain substantial benefits, and the lack of alternative approaches limits patient survival. Additionally, the absence of prognostic markers for well-differentiated tumors complicates patient-specific treatments and favors the progression of recurrent forms. In order to recognize the molecular basis involved in tumor dedifferentiation and identify potential markers for thyroid cancer prognosis prediction, we analysed the expression profile of 44 thyroid primary tumors with different degrees of dedifferentiation and aggressiveness using cDNA microarrays. Transcriptome comparison of dedifferentiated and well-differentiated thyroid tumors identified 1031 genes with >2-fold difference in absolute values and false discovery rate of o0.15. According to known molecular interaction and reaction networks, the products of these genes were mainly clustered in the MAPkinase signaling pathway, the TGF-b signaling pathway, focal adhesion and cell motility, activation of actin polymerization and cell cycle. An exhaustive search in several databases allowed us to identify various members of the matrix metalloproteinase, melanoma antigen A and collagen gene families within the upregulated gene set. We also identified a prognosis classifier comprising just 30 transcripts with an overall accuracy of 95%. These findings may clarify the molecular mechanisms involved in thyroid tumor dedifferentiation and provide a potential prognosis predictor as well as targets for new therapies.

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Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information

et al. 2007

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“…In addition, Ubp8-mediated deubiquitination of Snf1 promotes Snf1 activation on nonpreferred carbon sources and subsequent Snf1-mediated phosphorylation of specific downstream protein targets. understanding the role that USP22 and SAGA play in the death-from-cancer signature that is observed in various carcinomas (7,8).…”

Section: Vol 31 2011mentioning

confidence: 99%

“…Despite the lack of knowledge of the targets of many of these deubiquitinases, it is known that some of these enzymes impact cellular growth and function (3,21,46). Overexpression of certain deubiquitinases is associated with progression of malignancy in neuroblastomas and a variety of carcinomas, indicating that these enzymes may be oncogenic (27,31,38).USP22, a deubiquitinase associated with the SAGA histone acetyltransferase (HAT) complex, was identified as a member of an 11-gene "death-from-cancer" signature that serves as a predictor of treatment resistance, aggressive growth, and metastasis of human tumors when overexpressed (7,8). The SAGA complex is highly conserved, and its functions are best characterized in yeast (4,9,17,23,35).…”

mentioning

confidence: 99%

“…USP22, a deubiquitinase associated with the SAGA histone acetyltransferase (HAT) complex, was identified as a member of an 11-gene "death-from-cancer" signature that serves as a predictor of treatment resistance, aggressive growth, and metastasis of human tumors when overexpressed (7,8). The SAGA complex is highly conserved, and its functions are best characterized in yeast (4,9,17,23,35).…”

mentioning

confidence: 99%

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Ubp8 and SAGA Regulate Snf1 AMP Kinase Activity

Wilson

Koutelou

Hirsch

et al. 2011

Molecular and Cellular Biology

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Posttranslational modifications of histone proteins play important roles in the modulation of gene expression. The Saccharomyces cerevisiae (yeast) 2-MDa SAGA (Spt-Ada-Gcn5) complex, a well-studied multisubunit histone modifier, regulates gene expression through Gcn5-mediated histone acetylation and Ubp8-mediated histone deubiquitination. Using a proteomics approach, we determined that the SAGA complex also deubiquitinates nonhistone proteins, including Snf1, an AMP-activated kinase. Ubp8-mediated deubiquitination of Snf1 affects the stability and phosphorylation state of Snf1, thereby affecting Snf1 kinase activity. Others have reported that Gal83 is phosphorylated by Snf1, and we found that deletion of UBP8 causes decreased phosphorylation of Gal83, which is consistent with the effects of Ubp8 loss on Snf1 kinase functions. Overall, our data indicate that SAGA modulates the posttranslational modifications of Snf1 in order to fine-tune gene expression levels.Ubiquitination of cellular targets regulates many biological processes, from intracellular trafficking to gene expression. Although ubiquitination by ubiquitin (Ub) ligases is widely studied, less is known about subsequent deubiquitination (DUB) of cellular substrates. The identification of genes coding 16 deubiquitinases in the Saccharomyces cerevisiae (yeast) genome and genes coding at least 60 deubiquitinases in the human genome suggests that not only is deubiquitination important but also that deubiquitination may also occur in a substratespecific manner to regulate specific cellular processes. Despite the lack of knowledge of the targets of many of these deubiquitinases, it is known that some of these enzymes impact cellular growth and function (3,21,46). Overexpression of certain deubiquitinases is associated with progression of malignancy in neuroblastomas and a variety of carcinomas, indicating that these enzymes may be oncogenic (27,31,38).USP22, a deubiquitinase associated with the SAGA histone acetyltransferase (HAT) complex, was identified as a member of an 11-gene "death-from-cancer" signature that serves as a predictor of treatment resistance, aggressive growth, and metastasis of human tumors when overexpressed (7,8). The SAGA complex is highly conserved, and its functions are best characterized in yeast (4,9,17,23,35). In addition to acetylating histone H3 via the Gcn5 subunit, SAGA also proteolytically cleaves ubiquitin moieties from histone H2B via the Ubp8 subunit, which is an ortholog of USP22 (13, 47). Ubp8-mediated deubiquitination of histone H2B regulates the expression of target genes by modulating the level of histone H3 lysine 4 methylation, a mark that is associated with active transcription (13). In addition, Ubp8 facilitates the recruitment of the Cterminal domain kinase (Ctk1) to target gene promoters via histone H2B deubiquitination, which facilitates the transition from transcription initiation to elongation (43).Interestingly, recent studies indicate that the functions of USP22 extend beyond histone H2B, as it also deubiquiti...

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USP22 mediates the multidrug resistance of hepatocellular carcinoma via the SIRT1/AKT/MRP1 signaling pathway

Ling

Shan

et al. 2017

Mol Oncol

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Drug treatments for hepatocellular carcinoma (HCC) often fail because of multidrug resistance (MDR). The mechanisms of MDR are complex but cancer stem cells (CSCs), which are able to self‐renew and differentiate, have recently been shown to be involved. The deubiquitinating enzyme ubiquitin‐specific protease 22 (USP22) is a marker for CSCs. This study aimed to elucidate the role of USP22 in MDR of HCC and the underlying mechanisms. Using in vitro and in vivo assays, we found that modified USP22 levels were responsible for the altered drug‐resistant phenotype of BEL7402 and BEL/FU cells. Downregulation of USP22 dramatically inhibited the expression of ABCC1 (encoding MRP1) but weakly influenced ABCB1 (encoding P‐glycoprotein). Sirtuin 1 (SIRT1) was reported previously as a functional mediator of USP22 that could promote HCC cell proliferation and enhance resistance to chemotherapy. In this study, USP22 directly interacted with SIRT1 and positively regulated SIRT1 protein expression. Regulation of the expression of both USP22 and SIRT1 markedly affected the AKT pathway and MRP1 expression. Inhibition of the AKT pathway by its specific inhibitor LY294002 resulted in downregulation of MRP1. USP22 and MRP1 expression was detected in 168 clinical HCC samples by immunohistochemical staining, and a firm relationship between USP22 and MRP1 was identified. Together, these results indicate that USP22 could promote the MDR in HCC cells by activating the SIRT1/AKT/MRP1 pathway. USP22 might be a potential target, through which the MDR of HCC in clinical setting could be reversed.

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Genomic Models of Metastatic Cancer: Functional Analysis of Death-from-Cancer Signature Genes Reveals Aneuploid, Anoikis-Resistant, Metastasis-Enabling Phenotype with Altered Cell Cycle Control and Activated PcG Protein Chromatin Silencing Pathway

Cited by 154 publications

References 50 publications

Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information

Molecular profiling related to poor prognosis in thyroid carcinoma. Combining gene expression data and biological information

Ubp8 and SAGA Regulate Snf1 AMP Kinase Activity

USP22 mediates the multidrug resistance of hepatocellular carcinoma via the SIRT1/AKT/MRP1 signaling pathway

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