Frequent p16-Independent Inactivation of p14ARF in Human Melanoma

Freedberg, Daniel E.; Rigas, Sushilaben H.; Russak, Julie E.; Gai, Weiming; Kaplow, Margarita; Osman, Iman; Turner, Faye; Randerson-Moor, Juliette A.; Houghton, Alan N.; Busam, Klaus J.; Bishop, D. Timothy; Bastian, Boris C.; Newton-Bishop, Julia; Polsky, David

doi:10.1093/jnci/djn157

Cited by 97 publications

(84 citation statements)

References 41 publications

(45 reference statements)

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“…Similarly, using the criterion of a minimum 2-fold change after drug treatment, we have no evidence that the p14ARF promoter is methylated in any of the 7 cell lines tested in which the gene is not homozygously deleted. This observation contrasts with a recent study (Freedberg et al, 2008) describing methylation of the p14ARF promoter in some melanoma cell lines and metastases.…”

Section: Discussioncontrasting

confidence: 99%

Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

Bonazzi

Irwin

Hayward

2008

Genes Chromosomes & Cancer

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Tumor suppressor genes (TSGs) are sometimes inactivated by transcriptional silencing through promoter hypermethylation. To identify novel methylated TSGs in melanoma, we carried out global mRNA expression profiling on a panel of 12 melanoma cell lines treated with a combination of 5-Aza-2-deoxycytidine (5AzadC) and an inhibitor of histone deacetylase, Trichostatin A. Reactivation of gene expression after drug treatment was assessed using Illumina whole-genome microarrays. After qRT-PCR confirmation, we followed up 8 genes (AKAP12, ARHGEF16, ARHGAP27, ENC1, PPP1R3C, PPP1R14C, RARRES1, and TP53INP1) by quantitative DNA methylation analysis using mass spectrometry of base-specific cleaved amplification products in panels of melanoma cell lines and fresh tumors. PPP1R3C, ENC1, RARRES1, and TP53INP1, showed reduced mRNA expression in 35-59% of the melanoma cell lines compared to melanocytes and which was correlated with a high proportion of promoter methylation (>40-60%). The same genes also showed extensive promoter methylation in 6-25% of the tumor samples, thus confirming them as novel candidate TSGs in melanoma.

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Section: Discussioncontrasting

confidence: 99%

Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

Bonazzi

Irwin

Hayward

2008

Genes Chromosomes & Cancer

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“…Whereas p19 ARF is an exquisite sensor that is activated by oncogenic signals and mediates senescence in cultured murine cells, in human cells it does not seem to play a similarly dominant role (Wei et al 2001;Michaloglou et al 2005). Nonetheless, specific mutations affecting human ARF (i.e., p14 ARF ) but not p16 INK4A have been identified in some human melanoma (Freedberg et al 2008). Indeed, OIS mechanisms do not seem to be universal across cell types and genetic contexts.…”

Section: Oncogene-induced Senescence (Ois) In Vitromentioning

confidence: 99%

The essence of senescence: Figure 1.

Kuilman¹,

Michaloglou²,

Mooi³

et al. 2010

Genes Dev.

1,809

1,771

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Almost half a century after the first reports describing the limited replicative potential of primary cells in culture, there is now overwhelming evidence for the existence of “cellular senescence” in vivo. It is being recognized as a critical feature of mammalian cells to suppress tumorigenesis, acting alongside cell death programs. Here, we review the various features of cellular senescence and discuss their contribution to tumor suppression. Additionally, we highlight the power and limitations of the biomarkers currently used to identify senescent cells in vitro and in vivo.

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“…This has been shown to be a molecular predictor of cancer therapy outcome in prostate and breast cancers. 37 Therefore, in this study promoter methylation of three putative targets of the PcG protein/BMI1 driven pathway [20][21][22][23][24][25][26][27] ARF has been observed earlier in various types of tumours, including melanoma, 38 squamous cell carcinoma of the skin, 39 colon cancer 28 and head and neck cancer, 40 among others. It depends on the tumour type as to which promoter at the CDKN2a locus is methylated more frequently, as methylation of both promoters is regulated separately.…”

Section: Discussionmentioning

confidence: 55%

Inverse association of p16INK4a and p14ARF methylation of the CDKN2a locus in different Gleason scores of prostate cancer

Verdoodt

Sommerer

et al. 2011

Prostate Cancer Prostatic Dis

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BACKGROUND: Promoter hypermethylation is an important epigenetic mechanism in the regulation of several key modulators of prostate carcinoma progression. Recent studies suggest that the polycomb-group (PcG) protein BMI1 may have an impact on epigenetic regulation of several targets, including the CDKN2a locus. METHODS:In this study, we investigated the association of BMI1 expression, promoter methylation of CDKN2a (p16INK4a and p14 ARF ) and TMS1 with pathological variables (Gleason score, TNM stage, perineural invasion) in prostate cancer (PCa). RESULTS: Methylation of p16INK4a and p14 ARF revealed an inverse association with Gleason score 7b and Gleason score 6. No significant association could be demonstrated for BMI1 -overexpression and promoter methylation of p16INK4a , p14 ARF and TMS1 as well as pT category.CONCLUSIONS: Our data suggest that the CDKN2a locus is a switch in PCa with methylation of p16INK4a being a marker for more aggressive tumours of Gleason score 7b, but no association with BMI overexpression was observed.

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Frequent p16-Independent Inactivation of p14ARF in Human Melanoma

Abstract: Genetic and epigenetic analyses of the human 9p21 locus indicate that modifications of ARF occur independently of p16 inactivation in human melanoma and suggest that ARF is more frequently inactivated than p16.

Cited by 97 publications

References 41 publications

Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

Identification of candidate tumor suppressor genes inactivated by promoter methylation in melanoma

The essence of senescence: Figure 1.

Inverse association of p16INK4a and p14ARF methylation of the CDKN2a locus in different Gleason scores of prostate cancer

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