title: 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.
abstract: 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. In this study, we show that p15RS, through a 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 of Wnt/β-catenin-mediated transcription. Interestingly, overexpression of p15RS decreases the level of acetylated histone H3 in the c-MYC promoter. Finally, we demonstrate that p15RS significantly enhances the association of HDAC2 and TCF4 and enhances the occupancy of HDAC2 to 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.
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China, the State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China, the State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Yanquan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: the Department of Immunology, Third Military Medical School, Chongqing 610041, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China, the State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Yinyin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China, the State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Fangli
authors.initials: F
authors.lastname: Ren
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China, the F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
authors.forename: Yinyuan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China, the State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China.
authors.forename: Yarui
authors.initials: Y
authors.lastname: Feng
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China.
authors.forename: Fuqin
authors.initials: F
authors.lastname: Su
authors.affiliation: the Departments of Surgical Oncology and Pathology, Chinese PLA General Hospital, Beijing 100853, China, and.
authors.forename: Baoqing
authors.initials: B
authors.lastname: Jia
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China, the State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China, the Bioinformatics Division and Center for Synthetic and Systems Biology, Tsinghua University, Beijing 100084, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.affiliation: From the State Key Laboratory of Biomembrane and Membrane Biotechnology, School of Medicine, School of Life Sciences, National Engineering Laboratory for Anti-tumor Therapeutics, Tsinghua University, Beijing 100084, China, the State Key Laboratory of Biotherapy, Collaborative Innovation Center for Biotherapy, West China Hospital, Sichuan University, Sichuan 610041, China, zhijiec@tsinghua.edu.cn.
authors.forename: Zhijie
authors.initials: Z
authors.lastname: Chang
mesh_terms: D000107:Acetylation; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D018613:Microscopy, Confocal; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D018797:Cell Cycle Proteins; D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; C470426:RPRD1A protein, human; D012097:Repressor Proteins; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin; D019938:Cyclin D1; D056464:Histone Deacetylase 2
keywords: Histone Deacetylase (HDAC); Myc (c-Myc); Rprd1A; T-cell Factor (TCF); Wnt Signaling; p15RS; β-Catenin (B-Catenin)