2. Academic Validation
  3. Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influence on MEF2-dependent transcription

Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influence on MEF2-dependent transcription

  • Nucleic Acids Res. 2022 Mar 21;50(5):2566-2586. doi: 10.1093/nar/gkac081.
Martina Minisini 1,  Eros Di Giorgio 1,  Emanuela Kerschbamer 2,  Emiliano Dalla 1,  Massimo Faggiani 1,  Elisa Franforte 1,  Franz-Josef Meyer-Almes 3,  Rino Ragno 4,  Lorenzo Antonini 4,  Antonello Mai 5,  Francesco Fiorentino 5,  Dante Rotili 5,  Monica Chinellato 6,  Stefano Perin 7 8,  Laura Cendron 6,  Christian X Weichenberger 2,  Alessandro Angelini 7 8,  Claudio Brancolini 1
Affiliations

Affiliations

  • 1 Department of Medicine, Università degli Studi di Udine. P.le Kolbe 4, 33100 Udine Italy.
  • 2 Institute for Biomedicine, Eurac Research, Affiliated Institute of the University of Lübeck. Via Galvani 31, 39100 Bolzano, Italy.
  • 3 Department of Chemical Engineering and Biotechnology, University of Applied Science, Haardtring 100, 64295 Darmstadt, Germany.
  • 4 Rome Center for Molecular Design, Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy.
  • 5 Department of Chemistry and Technology of Drugs, "Sapienza" University of Rome, Piazzale Aldo Moro 5, Rome 00185, Italy.
  • 6 Department of Biology, University of Padova, Via U. Bassi, 58/B, 35121 Padova, Italy.
  • 7 Department of Molecular Sciences and Nanosystems, Ca' Foscari University of Venice, Via Torino 155, 30172 Mestre, Italy.
  • 8 European Centre for Living Technology (ECLT), Dorsoduro 3911, Calle Crosera, 30123 Venice, Italy.
PMID: 35150567 DOI: 10.1093/nar/gkac081
Abstract

In leiomyosarcoma class IIa HDACs (histone deacetylases) bind MEF2 and convert these transcription factors into repressors to sustain proliferation. Disruption of this complex with small molecules should antagonize Cancer growth. NKL54, a PAOA (pimeloylanilide o-aminoanilide) derivative, binds a hydrophobic groove of MEF2, which is used as a docking site by class IIa HDACs. However, NKL54 could also act as HDAC Inhibitor (HDACI). Therefore, it is unclear which activity is predominant. Here, we show that NKL54 and similar derivatives are unable to release MEF2 from binding to class IIa HDACs. Comparative transcriptomic analysis classifies these molecules as HDACIs strongly related to SAHA/vorinostat. Low expressed genes are upregulated by HDACIs, while abundant genes are repressed. This transcriptional resetting correlates with a reorganization of H3K27 acetylation around the transcription start site (TSS). Among the upregulated genes there are several BH3-only family members, thus explaining the induction of Apoptosis. Moreover, NKL54 triggers the upregulation of MEF2 and the downregulation of class IIa HDACs. NKL54 also increases the binding of MEF2D to promoters of genes that are upregulated after treatment. In summary, although NKL54 cannot outcompete MEF2 from binding to class IIa HDACs, it supports MEF2-dependent transcription through several actions, including potentiation of chromatin binding.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18361
    99.57%, HDAC Inhibitor