2. Academic Validation
  3. Inhibitor of CBP Histone Acetyltransferase Downregulates p53 Activation and Facilitates Methylation at Lysine 27 on Histone H3

Inhibitor of CBP Histone Acetyltransferase Downregulates p53 Activation and Facilitates Methylation at Lysine 27 on Histone H3

  • Molecules. 2018 Aug 2;23(8):1930. doi: 10.3390/molecules23081930.
Adam S Vincek 1 2,  Jigneshkumar Patel 3,  Anbalagan Jaganathan 4 5,  Antonia Green 6,  Valerie Pierre-Louis 7,  Vimal Arora 8,  Jill Rehmann 9,  Mihaly Mezei 10,  Ming-Ming Zhou 11,  Michael Ohlmeyer 12,  Shiraz Mujtaba 13 14
Affiliations

Affiliations

  • 1 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. [email protected].
  • 2 Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. [email protected].
  • 3 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. [email protected].
  • 4 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. [email protected].
  • 5 One Bungtown Rd, Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA. [email protected].
  • 6 Department of Physical Science, St. Joseph's College, 245 Clinton Avenue, Brooklyn, NY 11205, USA. [email protected].
  • 7 Department of Physical Science, St. Joseph's College, 245 Clinton Avenue, Brooklyn, NY 11205, USA. [email protected].
  • 8 Department of Biology, City University of New York, Medgar Evers College, Brooklyn, NY 11225, USA. [email protected].
  • 9 Department of Physical Science, St. Joseph's College, 245 Clinton Avenue, Brooklyn, NY 11205, USA. [email protected].
  • 10 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. [email protected].
  • 11 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. [email protected].
  • 12 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. [email protected].
  • 13 Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA. [email protected].
  • 14 Department of Biology, City University of New York, Medgar Evers College, Brooklyn, NY 11225, USA. [email protected].
PMID: 30072621 DOI: 10.3390/molecules23081930
Abstract

Tumor suppressor p53-directed Apoptosis triggers loss of normal cells, which contributes to the side-effects from Anticancer therapies. Thus, small molecules with potential to downregulate the activation of p53 could minimize pathology emerging from Anticancer therapies. Acetylation of p53 by the Histone Acetyltransferase (HAT) domain is the hallmark of coactivator CREB-binding protein (CBP) epigenetic function. During genotoxic stress, CBP HAT-mediated acetylation is essential for the activation of p53 to transcriptionally govern target genes, which control cellular responses. Here, we present a small molecule, NiCur, which blocks CBP HAT activity and downregulates p53 activation upon genotoxic stress. Computational modeling reveals that NiCur docks into the active site of CBP HAT. On CDKN1A promoter, the recruitment of p53 as well as RNA Polymerase II and levels of acetylation on histone H3 were diminished by NiCur. Specifically, NiCur reduces the levels of acetylation at lysine 27 on histone H3, which concomitantly increases the levels of trimethylation at lysine 27. Finally, NiCur attenuates p53-directed Apoptosis by inhibiting the Caspase 3 activity and cleavage of Poly (ADP-ribose) polymerase (PARP) in normal gastrointestinal epithelial cells. Collectively, NiCur demonstrates the potential to reprogram the chromatin landscape and modulate biological outcomes of CBP-mediated acetylation under normal and disease conditions.

Keywords

cy-C5-curcuminoids; histone acetylation; histone acetyltransferase; lysine acetylation; methylation; p53 acetylation; transcriptional coactivator CBP.

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