Epigenetic Silencing of the p16INK4a Tumor Suppressor Is Associated with Loss of CTCF Binding and a Chromatin Boundary

被引:179
作者
Witcher, Michael [1 ]
Emerson, Beverly M. [1 ]
机构
[1] Salk Inst Biol Studies, Regulatory Biol Lab, La Jolla, CA 92037 USA
关键词
ENHANCER-BLOCKING ACTIVITY; MAMMARY EPITHELIAL-CELLS; DNA METHYLATION; PROMOTER METHYLATION; BREAST-CANCER; PROTEIN CTCF; LUNG-CANCER; HYPERMETHYLATION; EXPRESSION; GENE;
D O I
10.1016/j.molcel.2009.04.001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The p16(INK4a) tumor suppressor gene is a frequent target of epigenetic inactivation in human cancers, which is an early event in breast carcinogenesis. We describe the existence of a chromatin boundary upstream of the p16 gene that is lost when this gene is aberrantly silenced. We show that the multifunctional protein CTCF associates in the vicinity of this boundary and absence of binding strongly coincides with p16 silencing in multiple types of cancer cells. CTCF binding also correlates with RASSF1A and CDH1 gene activation, and CTCF interaction is absent when these genes are methylated and silenced. Interestingly, defective poly(ADP-ribosyl)ation of CTCF and dissociation from the molecular chaperone Nucleolin occur in p 16-silenced cells, abrogating its proper function. Thus, destabilization of specific chromosomal boundaries through aberrant crosstalk between CTCF, poly(ADP-ribosyl)ation, and DNA methylation may be a general mechanism to inactivate tumor suppressor genes and initiate tumorigenesis in numerous forms of human cancers.
引用
收藏
页码:271 / 284
页数:14
相关论文
共 45 条
  • [21] A topoisomerase IIβ-mediated dsDNA break required for regulated transcription
    Ju, BG
    Lunyak, VV
    Perissi, V
    Garcia-Bassets, I
    Rose, DW
    Glass, CK
    Rosenfeld, MG
    [J]. SCIENCE, 2006, 312 (5781) : 1798 - 1802
  • [22] The regulation of INK4/ARF in cancer and aging
    Kim, William Y.
    Sharpless, Norman E.
    [J]. CELL, 2006, 127 (02) : 265 - 275
  • [23] Regulation of histone methylation by demethylimination and demethylation
    Klose, Robert J.
    Yi Zhang
    [J]. NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2007, 8 (04) : 307 - 318
  • [24] pRB family proteins are required for H3K27 trimethylation and polycomb repression complexes binding to and silencing p16INK4a tumor suppressor gene
    Kotake, Yojiro
    Cao, Ru
    Viatour, Patrick
    Sage, Julien
    Zhang, Yi
    Xiong, Yue
    [J]. GENES & DEVELOPMENT, 2007, 21 (01) : 49 - 54
  • [25] Transcriptional control by PARP-1: chromatin modulation, enhancer-binding, coregulation, and insulation
    Kraus, W. Lee
    [J]. CURRENT OPINION IN CELL BIOLOGY, 2008, 20 (03) : 294 - 302
  • [26] CTCF mediates interchromosomal colocalization between Igf2/H19 and Wsb1/Nf1
    Ling, JQ
    Li, T
    Hu, JF
    Vu, TH
    Chen, HL
    Qiu, XW
    Cherry, AM
    Hoffman, AR
    [J]. SCIENCE, 2006, 312 (5771) : 269 - 272
  • [27] p16INK4a prevents centrosome dysfunction and genomic instability in primary cells
    McDermott, KM
    Zhang, JM
    Holst, CR
    Kozakiewicz, BK
    Singla, V
    Tlsty, TD
    [J]. PLOS BIOLOGY, 2006, 4 (03) : 350 - 365
  • [28] Silenced tumor suppressor genes reactivated by DNA demethylation do not return to a fully euchromatic chromatin state
    McGarvey, KM
    Fahrner, JA
    Greene, E
    Martens, J
    Jenuwein, T
    Baylin, SB
    [J]. CANCER RESEARCH, 2006, 66 (07) : 3541 - 3549
  • [29] Nucleolin: a multiFACeTed protein
    Mongelard, Fabien
    Bouvet, Philippe
    [J]. TRENDS IN CELL BIOLOGY, 2007, 17 (02) : 80 - 86
  • [30] Frequent hypermethylation of p16 and p15 genes in multiple myeloma
    Ng, MHL
    Chung, YF
    Lo, KW
    Wickham, NWR
    Lee, JCK
    Huang, DP
    [J]. BLOOD, 1997, 89 (07) : 2500 - 2506