Polycomb CBX7 Directly Controls Trimethylation of Histone H3 at Lysine 9 at the p16 Locus

Li, Qiang; Wang, Xiuhong; Lu, Zheming; Zhang, Baozhen; Guan, Zhenpo; Liu, Zhaojun; Zhong, Qiming; Gu, Lin; Zhou, Jing; Zhu, Budong; Ji, Jiafu; Deng, Dajun

doi:10.1371/journal.pone.0013732

Cited by 54 publications

(50 citation statements)

References 33 publications

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“…We also cannot exclude the hypothesis that the shRNA constructs used in the previous studies may have interfered with the expression of other genes, maybe of the Pc family. The behavior of MEFs derived from Cbx7-KO mice and Cbx7-overexpressing transgenic mice described herein is supported by the drastic downregulation of CBX7 expression previously reported by several groups in malignant neoplasias -including thyroid (6), pancreatic (8), colon (11), lung (present study), gastric (10), bladder (7), and breast (9) carcinomas -and by a reduced growth rate achieved by restoration of CBX7 expression in carcinoma cells of different origin (6,9,11,38).…”

Section: Discussionsupporting

confidence: 85%

CBX7 is a tumor suppressor in mice and humans

Forzati¹,

Federico²,

Pallante³

et al. 2012

J. Clin. Invest.

139

158

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The CBX7 gene encodes a polycomb group protein that is known to be downregulated in many types of human cancers, although the role of this protein in carcinogenesis remains unclear. To shed light on this issue, we generated mice null for Cbx7. Mouse embryonic fibroblasts derived from these mice had a higher growth rate and reduced susceptibility to senescence compared with their WT counterparts. This was associated with upregulated expression of multiple cell cycle components, including cyclin E, which is known to play a key role in lung carcinogenesis in humans. Adult Cbx7-KO mice developed liver and lung adenomas and carcinomas. In in vivo and in vitro experiments, we demonstrated that CBX7 bound to the CCNE1 promoter in a complex that included HDAC2 and negatively regulated CCNE1 expression. Finally, we found that the lack of CBX7 protein expression in human lung carcinomas correlated with CCNE1 overexpression. These data suggest that CBX7 is a tumor suppressor and that its loss plays a key role in the pathogenesis of cancer.

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Section: Discussionsupporting

confidence: 85%

CBX7 is a tumor suppressor in mice and humans

Forzati¹,

Federico²,

Pallante³

et al. 2012

J. Clin. Invest.

139

158

View full text Add to dashboard Cite

show abstract

“…Polycomb group (PcG) proteins and other factors play important roles in the regulation of p16 expression (Gil and Peters, 2006;Deng et al, 2010;Li et al, 2010). In the 293T cells transiently transfected with p16ATF-6I, we found that the transcription level of the p16 activator Ets2 gene was slightly increased and that of the repressor Suz12 gene was significantly decreased.…”

Section: Discussionmentioning

confidence: 96%

“…ChIP assays were performed and analyzed essentially as described (Shang et al, 2000;Li et al, 2010). The antibodies used were rabbit anti-trimethylated H3K4 (H3K4me3; no.…”

Section: Chromatin Immunoprecipitation (Chip) Assaymentioning

confidence: 99%

The p16-Specific Reactivation and Inhibition of Cell Migration Through Demethylation of CpG Islands by Engineered Transcription Factors

et al. 2012

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Methylation of CpG islands inactivates transcription of tumor suppressor genes including p16 (CDKN2A). Inhibitors of DNA methylation and histone deacylation are recognized as useful cancer therapeutic chemicals through reactivation of the expression of methylated genes. However, these inhibitors are not target genespecific, so that they lead to serious side effects as regular cytotoxic chemotherapy agents. To explore the feasibility of methylated gene-specific reactivation by artificial transcription factors, we engineered a set of Sp1-like seven-finger zinc-finger proteins (7ZFPs) targeted to a 21-bp sequence of the p16 promoter and found that these 7ZFPs could bind specifically to the target p16 promoter probe. Then the p16-specific artificial transcription factors (p16ATFs) were made from these 7ZFPs and the transcription activator VP64. Results showed that transient transfection of some p16ATFs selectively up-regulated the endogenous p16 expression in the p16-active 293T cells. Moreover, the transient transfection of the representative p16ATF-6I specifically reactivated p16 expression in the p16-methylated H1299 and AGS cells pretreated with a nontoxic amount of 5'-azadeoxycytidine (20 and 80 nM, respectively). In addition, stable transfection of the p16ATF induced demethylation of p16 CpG island and trimethylation of histone H3K4, and inhibited recruitment of DNA methyltransferase 1 and trimethylation of H3K9 and H3K27 in the p16 promoter in H1299 cells without 5'-aza-deoxycytidine pretreatment. Notably, inhibition of cell migration and invasion was observed in these p16-reactivated cells induced by transient and stable p16ATF transfection. These results demonstrate that p16ATF not only specifically reactivates p16 expression through demethylation of CpG islands, but also restores methylated p16 function.

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“…However, various mechanisms may influence ARF and p27 KIP1 up-regulation during senescence. For instance, ARF can be restored by the removal of the Polycomb genes BMI1 and CBX7 (28,29), and p27 KIP1 can be degraded by the E3 ligase Skp2 (30). Rb has a nonredundant role in senescent cells by mediating heterochromatin formation at E2F1 targets.…”

Section: Discussionmentioning

confidence: 99%

The Retinoblastoma Protein Selectively Represses E2F1 Targets via a TAAC DNA Element during Cellular Senescence

Chen

Xue

Niu

et al. 2012

Journal of Biological Chemistry

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Background: Expression patterns of E2F1 target genes differ during cellular senescence. Results: Rb protein selectively represses specific E2F1 target genes via a TAAC element in senescent cells. Conclusion: Cellular senescence is influenced by selective repression of E2F1 target transcription by Rb. Significance: An understanding of how E2F1 target genes that participate in proliferation are regulated is crucial for elucidating the mechanisms of cellular senescence.

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Polycomb CBX7 Directly Controls Trimethylation of Histone H3 at Lysine 9 at the p16 Locus

Cited by 54 publications

References 33 publications

CBX7 is a tumor suppressor in mice and humans

CBX7 is a tumor suppressor in mice and humans

The p16-Specific Reactivation and Inhibition of Cell Migration Through Demethylation of CpG Islands by Engineered Transcription Factors

The Retinoblastoma Protein Selectively Represses E2F1 Targets via a TAAC DNA Element during Cellular Senescence

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