Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

Morris, Mark R.; Ricketts, Christopher J.; Gentle, Dean; McRonald, Fiona E.; Carli, Natasha; Khalili, Hafez; Brown, Michael D.; Kishida, Takeshi; Yao, Masahiro; Banks, Rosamonde E.; Clarke, Noel W.; Latif, Farida; Maher, Eamonn R.

doi:10.1038/onc.2010.525

Cited by 180 publications

(142 citation statements)

References 49 publications

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“…1C). Although p90/CCDC8 has been reported as a candidate tumor suppressor gene in renal cell carcinoma (RCC), the molecular function of this protein is unclear (25).…”

Section: Resultsmentioning

confidence: 99%

“…In this regard, p90 has also been identified as a candidate tumor suppressor gene as hypermethylation and transcriptional silencing of the p90 promoter was found in 35% of primary RCC tumor samples (25). It will be interesting to test whether p53-mediated apoptosis is abrogated in the human tumors lacking p90 expression and whether reactivation of silenced p90 promotes apoptosis thereby contributing to tumor suppression.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Dai

Tang

Jung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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p53 functions as a central node for organizing whether the cell responds to stress with apoptosis or cell cycle arrest; however, the molecular events that lead to apoptotic responses are not completely understood. Here, we identified p90 (also called Coiled-Coil Domain Containing 8) as a unique regulator for p53. p90 has no obvious effects on either the levels of p53 or p53-mediated cell cycle arrest but is specifically required for p53-mediated apoptosis upon DNA damage. Notably, p90 is crucial for Tip60-dependent p53 acetylation at Lys120, therefore facilitating activation of the proapoptotic targets. These studies indicate that p90 is a critical cofactor for p53-mediated apoptosis through promoting Tip60-mediated p53 acetylation.T he p53 tumor suppressor acts as the major sensor for a regulatory circuit that monitors signaling pathways from diverse sources, including DNA damage, oncogenic events, and other abnormal cellular processes (1, 2). p53 monitors and responds to a multitude of stress signals by coordinating cell growth arrest or apoptosis (3-5). Central to p53 regulation of these cellular processes is its activity as a transcription factor, although transcription-independent functions of p53 are also critical under some biological settings. The activation of p53 transcription activity requires multiple steps, including sequence-specific DNA binding, antirepression and acquirement of combinations of posttranslational modifications, and recruitment of corepressors/coactivators in a promoter-specific manner (6). To suppress tumor growth, p53 induces either cell growth arrest or apoptosis depending on the cellular context. The molecular mechanisms that govern the choice between growth arrest and apoptosis are extremely important but not well understood (4, 7). As a key player in the stress response, p53 demands an exquisitely complicated network of control and fine-tuning mechanisms to ensure correct, differentiated responses to the various stress signals encountered by cells (2,5,(8)(9)(10).p53 was the first nonhistone protein known to be regulated by acetylation and deacetylation (11,12). There is accumulating evidence indicating that acetylation of p53 plays a major role in activating p53 function during stress responses (2, 13, 14). Following our early findings of C terminus p53 acetylation, we and others recently showed that p53 is also acetylated by Tip60 (also known as KAT5)/MOF (human ortholog of males absent on the first) at residue Lys120 (K120) within the DNA-binding domain (15-17). K120 acetylation is crucial for p53-mediated apoptosis but has no obvious effect on p21 expression, an essential target of p53-mediated growth arrest. Notably, although Tip60 is required for K120 acetylation of p53 in vivo, the levels of K120 acetylation are dynamically regulated in vivo and the interaction between p53 and Tip60 is not very stable, indicating that additional regulators may play a role in controlling K120 acetylation and subsequent p53-mediated apoptotic response (18)(19)(20). Through biochemical pur...

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“…1C). Although p90/CCDC8 has been reported as a candidate tumor suppressor gene in renal cell carcinoma (RCC), the molecular function of this protein is unclear (25).…”

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Differential effects on p53-mediated cell cycle arrest vs. apoptosis by p90

Dai

Tang

Jung

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

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“…[52][53][54] Although many of the novel genes we identified have not been previously reported in bladder cancer, their inappropriate methylation, accompanied with gene-silencing, has been reported in the context of other tumor types and suggests potential roles as tumor suppressor genes. 55,56,57 To determine associations between methylation and gene expression, we confined our studies to genes showing frequent and/or high mean levels of methylation. For the majority of gene-transcripts we investigated, promoter methylation was negatively correlated with reduced transcript expression, although not significantly so (data not shown).…”

Section: Discussionmentioning

confidence: 99%

936 Quantitative genome-wide methylation analysis of high-grade non-muscle invasive bladder cancer

Kitchen¹,

Bryan²,

Emes³

et al. 2016

European Urology Supplements

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High-grade non-muscle invasive bladder cancer (HG-NMIBC) is a clinically unpredictable disease with greater risks of recurrence and progression relative to their low-intermediate-grade counterparts. The molecular events, including those affecting the epigenome, that characterize this disease entity in the context of tumor development, recurrence, and progression, are incompletely understood. We therefore interrogated genome-wide DNA methylation using HumanMethylation450 BeadChip arrays in 21 primary HG-NMIBC tumors relative to normal bladder controls. Using strict inclusion-exclusion criteria we identified 1,057 hypermethylated CpGs within gene promoter-associated CpG islands, representing 256 genes. We validated the array data by bisulphite pyrosequencing and examined 25 array-identified candidate genes in an independent cohort of 30 HG-NMIBC and 18 low-intermediate-grade NMIBC. These analyses revealed significantly higher methylation frequencies in high-grade tumors relative to lowintermediate-grade tumors for the ATP5G2, IRX1 and VAX2 genes (P<0.05), and similarly significant increases in mean levels of methylation in high-grade tumors for the ATP5G2, VAX2, INSRR, PRDM14, VSX1, TFAP2b, PRRX1, and HIST1H4F genes (P<0.05). Although inappropriate promoter methylation was not invariantly associated with reduced transcript expression, a significant association was apparent for the ARHGEF4, PON3, STAT5a, and VAX2 gene transcripts (P<0.05). Herein, we present the first genome-wide DNA methylation analysis in a unique HG-NMIBC cohort, showing extensive and discrete methylation changes relative to normal bladder and low-intermediate-grade tumors. The genes we identified hold significant potential as targets for novel therapeutic intervention either alone, or in combination, with more conventional therapeutic options in the treatment of this clinically unpredictable disease.

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“…However, from other studies it has become apparent, that numerous epigenetic alterations are also involved in renal carcinogenesis (Baldewijns et al, 2008;Morris et al, 2008Morris et al, , 2010Morris et al, , 2011. Most of these alterations refer to changed DNA methylation as observed in CGI of various genes and some of them have been suggested in functional analyses as candidate tumour suppressor genes (TSG) function (Dreijerink et al, 2001;Morris et al, 2010Morris et al, , 2011.…”

mentioning

confidence: 99%

“…Most of these alterations refer to changed DNA methylation as observed in CGI of various genes and some of them have been suggested in functional analyses as candidate tumour suppressor genes (TSG) function (Dreijerink et al, 2001;Morris et al, 2010Morris et al, , 2011. Changes in clinical outcome of RCC patients have been attributed so far either to multimarker methylation panels (Urakami et al, 2006) or to gene-specific CGI methylation of genes such as basonuclin 1 (BNC1), collagen type XIV a 1 (COL14A1), DAL-1/4.1B, GATA-binding protein 5 (GATA5), secreted frizzled-related protein 1 (SFRP1) and signal peptide CUB domain EGF-like 3 (SCUBE3) (Yamada et al, 2006;Morris et al, 2010;Peters et al, 2012).…”

mentioning

confidence: 99%