ArticleNucleic acids research2022
Transcriptomic and genomic studies classify NKL54 as a histone deacetylase inhibitor with indirect influence on MEF2-dependent transcription.
Article in Nucleic acids research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 26 citations in OpenAlex.
- The Diverse Roles of the MEF2 Transcription Factor Family in Tumor Progression and Emerging Therapeutic Opportunities.Biomedicines · 2026Review
- Development of Biphenyl-Substituted Uracil-Based Hydroxamic Acids (UBHAs) as Potent HDAC Inhibitors with Pro-Apoptotic Activity in Leukemia and Prostate Cancer Cells.Journal of medicinal chemistry · 2026Article
- Class IIa HDACs forced degradation allows resensitization of oxaliplatin-resistant FBXW7-mutated colorectal cancer.Molecular oncology · 2026Article
- HDAC7-Induced Epigenetic Repression Modulates ATF3 Functional Plasticity in Colorectal Cancer Pathogenesis.International journal of biological sciences · 2026Article
- Identification of a novel minor-groove DNA binder that represses mitochondrial gene expression and induces apoptosis in highly aggressive leiomyosarcoma cells.Cell death discovery · 2025Article
- Development of C646-Based Proteolysis Targeting Chimeras Degraders of the Lysine Acetyltransferases CBP and p300.ChemMedChem · 2025Article
- HDAC9 Deficiency Upregulates cGMP-dependent Kinase II to Mitigate Neuronal Apoptosis in Ischemic Stroke.Translational stroke research · 2025Article
- Activation and inhibition of sirtuins: From bench to bedside.Medicinal research reviews · 2025Review
- HDAC4 influences the DNA damage response and counteracts senescence by assembling with HDAC1/HDAC2 to control H2BK120 acetylation and homology-directed repair.Nucleic acids research · 2024Article
- Activation of CaCell death and differentiation · 2024Article
- Acetylation and Phosphorylation in the Regulation of Hypoxia-Inducible Factor Activities: Additional Options to Modulate Adaptations to Changes in Oxygen Levels.Life (Basel, Switzerland) · 2023Review
- HDAC4 in cancer: A multitasking platform to drive not only epigenetic modifications.Frontiers in molecular biosciences · 2023Review
- Proteotoxic stress-induced apoptosis in cancer cells: understanding the susceptibility and enhancing the potency.Cell death discovery · 2022Article
- Comparative whole transcriptome analysis of gene expression in three canine soft tissue sarcoma types.PloS one · 2022Article
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Authors and funding
18 authors at 5 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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