Epigenetic regulation of the<i>INK4b-ARF-INK4a</i>locus

Popov, Nikolay; Gil, Jesús

doi:10.4161/epi.5.8.12996

Cited by 182 publications

(165 citation statements)

References 73 publications

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“…Non-coding transcripts may have a role in vascular diseases, as was recently demonstrated for the ANRIL transcript. 28 A rare large duplication of the MYH11/ABCC6 locus that was also found in patients with aortic dissections was not analyzed in our study as this CNV has a frequency of about 1/1000 in the normal population. 11 However, such a low frequency does not rule out that this CNV is associated with an increased risk for CeAD.…”

Section: Discussionmentioning

confidence: 99%

Copy number variation in patients with cervical artery dissection

et al. 2012

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Section: Discussionmentioning

confidence: 99%

Copy number variation in patients with cervical artery dissection

et al. 2012

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“…Increased ANRIL expression levels were observed in prostate carcinomas and involved in repression of the CDKN2B/CDKN2A/ARF gene cluster in cis by directly binding to PRC complexes (10). EZH2 (PRC2) and CBX7 (PRC1) act as transcriptional repressors of many genes and are particularly implicated in silencing via ANRIL of the CDKN2B/CDKN2A/ ARF locus (12). However, the functional role and underlying mechanism of action of ANRIL in breast carcinogenesis still remain unclear (13).…”

Section: Introductionmentioning

confidence: 99%

Expression of ANRIL–Polycomb Complexes–CDKN2A/B/ARF Genes in Breast Tumors: Identification of a Two-Gene (EZH2/CBX7) Signature with Independent Prognostic Value

Meseure

Vacher

Alsibai

et al. 2016

Molecular Cancer Research

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ANRIL, a long noncoding RNA (lncRNA), has recently been reported to have a direct role in recruiting polycomb repressive complexes PRC2 and PRC1 to regulate the expression of the p15/CDKN2B-p16/CDKN2A-p14/ARF gene cluster. Expression analysis of ANRIL, EZH2, SUZ12, EED, JARID2, CBX7, BMI1, p16, p15, and p14/ARF genes was evaluated in a large cohort of invasive breast carcinomas (IBC, n ¼ 456) by qRT-PCR and immunohistochemistry (IHC) was performed on CBX7, EZH2, p14, p15, p16, H3K27me3, and H3K27ac. We observed significant overexpression in IBCs of ANRIL (19.7%) and EZH2 (77.0%) and an underexpression of CBX7 (39.7%). Correlations were identified between these genes, their expression patterns, and several classical clinical and pathologic parameters, molecular subtypes, and patient outcomes, as well as with proliferation, epithelial-mesenchymal transition, and breast cancer stem cell markers. Multivariate analysis revealed that combined EZH2/ CBX7 status is an independent prognostic factor (P ¼ 0.001). In addition, several miRNAs negatively associated with CBX7 underexpression and EZH2 overexpression. These data demonstrate a complex pattern of interactions between lncRNA ANRIL, several miRNAs, PRC2/PRC1 subunits, and p15/CDKN2B-p16/CDKN2A-p14/ARF locus and suggest that their expression should be considered together to evaluate antitumoral drugs, in particular the BET bromodomain inhibitors.Implications: This study suggests that the global pattern of expression rather than expression of individual family members should be taken into account when defining functionality of repressive Polycomb complexes and therapeutic targeting potential.

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“…Activation of pRB in response to OIS occurs through transcriptional induction of the cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitor and tumor suppressor p16 INK4A . In normal cells p16 INK4A transcription is epigenetically repressed through a polycomb repressive complex-dependent mechanism (16). OIS causes KDM6B-mediated H3K27 demethylation and increased p16 INK4A expression, which in turn causes G1 arrest and senescence through activation of the pRB tumor suppressor (11,12).…”

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Tumor suppressor p16 ^INK4A is necessary for survival of cervical carcinoma cell lines

McLaughlin-Drubin

Park²,

Münger

2013

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

149

153

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The tumor suppressor p16 INK4A inhibits formation of enzymatically active complexes of cyclin-dependent kinases 4 and 6 (CDK4/6) with D-type cyclins. Oncogenic stress induces p16 INK4A expression, which in turn triggers cellular senescence through activation of the retinoblastoma tumor suppressor. Subversion of oncogene-induced senescence is a key step during cancer development, and many tumors have lost p16 INK4A activity by mutation or epigenetic silencing. Human papillomavirus (HPV)-associated tumors express high levels of p16 INK4A in response to E7 oncoprotein expression. Induction of p16 INK4A expression is not a consequence of retinoblastoma tumor suppressor inactivation but is triggered by a cellular senescence response and is mediated by epigenetic derepression through the H3K27-specific demethylase (KDM)6B. HPV E7 expression causes an acute dependence on KDM6B expression for cell survival. The p16 INK4A tumor suppressor is a critical KDM6B downstream transcriptional target and its expression is critical for cell survival. This oncogenic p16 INK4A activity depends on inhibition of CDK4/CDK6, suggesting that in cervical cancer cells where retinoblastoma tumor suppressor is inactivated, CDK4/CDK6 activity needs to be inhibited in order for cells to survive. Finally, we note that HPV E7 expression creates a unique cellular vulnerability to small-molecule KDM6A/B inhibitors.synthetic lethality | apoptosis | biomarker | cancer therapy P osttranslational histone modifications, including phosphorylation, ubiquitination, acetylation, and methylation, impact both the physical state and the transcriptional competence of chromatin. These modifications are dynamic and regulate a variety of cellular processes, such as stem cell maintenance, cell fate determination and maintenance, cell cycle control, and epigenetic heritability of transcriptional programs (reviewed in refs. 1 and 2). Methylation of lysine residues on histones is modulated by histone lysine methyltransferases (KMTs) and histone lysine demethylases (KDMs). Although histone lysine methylation is involved in both transcriptional activation and repression, histone H3 trimethylation of lysine 27 (H3K27me3) on gene promoters is crucial for epigenetic silencing mediated by polycomb group proteins (3-5). The JmjC-domain containing histone demethylases, KDM6A (UTX) and KDM6B (JMJD3) remove this repressive mark, allowing for transcriptional activation (6-10). Although KDM6A and KDM6B appear identical with regards to catalytic activities and histone substrate specificities, they have a number of nonoverlapping and nonredundant biological activities. KDM6B-but not KDM6A-regulates RAS/RAF-mediated oncogene-induced senescence (OIS) (11, 12). OIS was originally described as a cell-abortive response to ectopic RAS oncogene expression in normal human cells. It is now recognized that OIS represents one of several cell-intrinsic tumor-suppressor responses that function to eliminate aberrantly proliferating, potentially premalignant cells. Evidence for OIS has been dete...

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Epigenetic regulation of theINK4b-ARF-INK4alocus

Cited by 182 publications

References 73 publications

Copy number variation in patients with cervical artery dissection

Copy number variation in patients with cervical artery dissection

Expression of ANRIL–Polycomb Complexes–CDKN2A/B/ARF Genes in Breast Tumors: Identification of a Two-Gene (EZH2/CBX7) Signature with Independent Prognostic Value

Tumor suppressor p16 ^INK4A is necessary for survival of cervical carcinoma cell lines

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Epigenetic regulation of theINK4b-ARF-INK4alocus

Cited by 182 publications

References 73 publications

Copy number variation in patients with cervical artery dissection

Copy number variation in patients with cervical artery dissection

Expression of ANRIL–Polycomb Complexes–CDKN2A/B/ARF Genes in Breast Tumors: Identification of a Two-Gene (EZH2/CBX7) Signature with Independent Prognostic Value

Tumor suppressor p16 INK4A is necessary for survival of cervical carcinoma cell lines

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Tumor suppressor p16 ^INK4A is necessary for survival of cervical carcinoma cell lines