TY - JOUR
T1 - P15RS/RPRD1A (p15INK4b-related sequence/regulation of nuclear pre-mRNA domain-containing protein 1A) interacts with HDAC2 in inhibition of the Wnt/β-catenin signaling pathway
AU - Liu, Chunxiao
AU - Zhang, Yanquan
AU - Li, Jun
AU - Wang, Yinyin
AU - Ren, Fangli
AU - Zhou, Yifan
AU - Wu, Yinyuan
AU - Feng, Yarui
AU - Zhou, Yu
AU - Su, Fuqin
AU - Jia, Baoqing
AU - Wang, Dong
AU - Chang, Zhijie
N1 - Publisher Copyright:
© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2015/4/10
Y1 - 2015/4/10
N2 - We previously reported that p15RS (p15INK4b-related sequence), a regulation of nuclear pre-mRNA domain containing protein, inhibited Wnt signaling by interrupting the formation of the β-catenin•TCF4 complex. However, how p15RS functions as an intrinsic repressor to repress transcription remains unclear. Inthis study,weshowthatp15RS,througha specific interaction with HDAC2 (histone deacetylase 2), a deacetylase that regulates gene transcription, maintains histone H3 in a deacetylated state in the promoter region of Wnt-targeted genes where β-catenin•TCF4 is bound. We observed that histone deacetylase inhibitors impair the ability of p15RS in inhibiting Wnt/β-catenin signaling. Depletion of HDAC2 markedly disabled p15RS inhibition ofWnt/β-catenin-mediated transcription. Interestingly, overexpression of p15RS decreases the level of acetylated histoneH3in the c-MYC promoter. Finally, we demonstrate that p15RS significantlyenhancesthe association ofHDAC2andTCF4andenhances the occupancy ofHDAC2to DNA, resulting in the deacetylation of histone H3 and the failure of β-catenin interaction. We propose that p15RS acts as an intrinsic transcriptional repressor for Wnt/ β-catenin-mediated gene transcription at least partially through recruiting HDAC2 to occupy the promoter and maintaining deacetylated histone H3.
AB - We previously reported that p15RS (p15INK4b-related sequence), a regulation of nuclear pre-mRNA domain containing protein, inhibited Wnt signaling by interrupting the formation of the β-catenin•TCF4 complex. However, how p15RS functions as an intrinsic repressor to repress transcription remains unclear. Inthis study,weshowthatp15RS,througha specific interaction with HDAC2 (histone deacetylase 2), a deacetylase that regulates gene transcription, maintains histone H3 in a deacetylated state in the promoter region of Wnt-targeted genes where β-catenin•TCF4 is bound. We observed that histone deacetylase inhibitors impair the ability of p15RS in inhibiting Wnt/β-catenin signaling. Depletion of HDAC2 markedly disabled p15RS inhibition ofWnt/β-catenin-mediated transcription. Interestingly, overexpression of p15RS decreases the level of acetylated histoneH3in the c-MYC promoter. Finally, we demonstrate that p15RS significantlyenhancesthe association ofHDAC2andTCF4andenhances the occupancy ofHDAC2to DNA, resulting in the deacetylation of histone H3 and the failure of β-catenin interaction. We propose that p15RS acts as an intrinsic transcriptional repressor for Wnt/ β-catenin-mediated gene transcription at least partially through recruiting HDAC2 to occupy the promoter and maintaining deacetylated histone H3.
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U2 - 10.1074/jbc.M114.620872
DO - 10.1074/jbc.M114.620872
M3 - Article
C2 - 25697359
AN - SCOPUS:84926646893
SN - 0021-9258
VL - 290
SP - 9701
EP - 9713
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 15
ER -