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HDACs in Epigenetics and Disease

Histone deacetylases (HDACs) are enzymes that regulate gene activity by modifying chromatin structure. They work by removing acetyl groups from histone proteins, which causes DNA to wrap more tightly around these proteins and makes genes less accessible for transcription. In this way, HDACs generally act as gene repressors. They play important roles in processes like cell growth, differentiation, and development, and their dysregulation is linked to diseases such as cancer and neurological disorders, making them important targets for therapeutic drugs.

 
Protein / Family Epigenetic Function Disease Association Key Publications Key Products
α-tubulin (HDAC6 substrate) – Cytoskeletal protein Acetylation affects microtubule stability Neurodegeneration Li et al., J. Neurol. Sci. 2011.
CBP (CREBBP) Co-activator protein Histone acetyltransferase (HAT), Binds to phosphorylated CREB (at Ser133), acts as a scaffold and chromatin modifier Rubinstein-Taybi syndrome (mutations in CBP/CREBBP), Cancer, Intellectual disability Zhong et al., Mol. Cell. 2002.
Ishihama et al., BMJ. 2026.
FOX Transcription factors (Forkhead box family). Bind DNA and control gene on/off regulation. Repressors that recruit HDAC containing complexes. Developmental and verban dyzpraxia, IPEX syndrome, Autism spectrum disorders, and cancer (breast and prostrate) Krause et al., Blood. 2020.
HDACs(1-10) Zn²⁺-dependent, histone/ non-histone deacetlation, transcriptional repression, Antagonize p300 Cancer (e.g., leukemia, colon, prostate), neurodegeneration, skeletal muscle atrophy, immune disorders Cheng et al., Eur J Med Chem., 2024
Mazzocchi et al., Brain Behav Immun. 2022
Habibian et al., ell Signal. 2023
HSP90 (HDAC6 substrate) – Chaperone protein HDAC6 substrate. Chaperone protein Regulated by acetylation status. Cancer Giommarelli et al., Cell. Mol. Life Sci. 2009.
NCOR Transcriptional repression of hormone-responsive genes. Nuclear receptor co-repressor Neurodevelopmental disorders, Thyroid hormone resistance, cancer and Metabolic disorders Paluvai et al., Mol. Biosci. 2023.
NuRD Complex (e.g., CHD4, MTA1/2) – Chromatin remodeling + deacetylation Couples ATP-dependent remodeling with HDAC activity. Deacetylation Cancer, developmental disorders Fu et al., Clin. Exp. Med. 2026.
p300 Histone acetyltransferase (HAT), Acetylates lysine residues on histone tails (e.g., H3K27ac), transcriptional co-activator & modulates chromatin structure to enhance gene expression Mutations found in various cancers, Rubinstein Syndrome, Neurodevelopmental Disorders, Inflammation & Viral Infections Zhang et al., Dev Cell. 2016
Chen et al., J Neuropathol Exp Neurol. 2025 "
p53 Deacetylation reduces transcriptional activity. Tumor suppressor transcription factor, Regulates DNA damage response, p300 directly binds and acetylates p53 enhancing its transcriptional activity. Almost all major cancers (mutated in >50% of human tumors), Li-Fraumeni syndrome, Neurodegenerative diseases (e.g., Alzheimer’s) Chen et al., Oncogene. 2025
Liu et al., Nat Rev Mol Cell Biol. 2025
SIN3A (co-repressor scaffold) – Core platform for HDAC1/2 complexes Transcriptional co-repressor scaffold protein. Recruits HDACs to chromatin Cancer, nerodevelopment disorders, metabolic stress pathways. Yang et al., J. Mol. Cell Biol. 2018
Sirtuins: (SIRT1–7) NAD⁺-dependent deacetylases, Metabolic and stress response regulators, SIRT1 deacetylates p300 Aging, metabolic diseases, cancer, cardiovascular diseases Ding et al., Circ Res. 2025
Zhra et al., Cells. 2025
Yu et al., Front Oncol. 2024