Histone deacetylases and PET

Histone deacetylases (HDACs) catalyse the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. Deacetylation of nonhistone proteins, including nuclear receptors, controls diverse cellular processes. Also some sirtuins deacetylate protein lysine residues.

DNA transcription is influenced by the packaging of DNA into chromatin. The architecture of nucleosome, consisting of 146 bp of DNA and an octamer of histones, is modified by methylation, phosphorylation, and acetylation of histones. Transcriptionally active chromatin is hyperacetylated. Deacetylation by HDACs causes chromatin condensation and blocks the transcriptional proteins from accessing the DNA.

HDACs are also subject to post-transitional modifications by phosphorylation, acetylation, ubiquitylation, and sumoylation, affecting their activity. Histone deacetylase inhibitors (HDIs) have been used as anti-epileptics and anticancer agents, and show promise in epigenetic-based therapies of many diseases. Ketone body β-hydroxybutyrate (β-HB) is an endogenous inhibitor of HDACs.

[11C]Martinostat is selective for class I HDACs (HDAC1, HDAC2, and HDAC3), which are implicated in regulating neuroplasticity and cognitive function, and can be used to assess the density and occupancy of these HDACs in the brain (Wei et al., 2015). For instance, [11C]Martinostat PET has revealed reduced HDAC availability in schizophrenia (Gilbert et al., 2019) and Alzheimer's disease (Pascoal et al., 2022).

[18F]FAHA shows highest substrate affinity to class IIa HDACs (HDAC4, HDAC5, HDAC7, and HDAC9). In the brain cells, [18F]FAHA is metabolized to [18F]fluoroacetate and further anabolized to [18F]citrate, which are trapped in cells; thus [18F]FAHA PET could be used to assess the class IIa HDAC inhibitors (Yeh et al., 2013).


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Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014; 6(4): a018713. doi: 10.1101/cshperspect.a018713.

Wey HY, Gilbert TM, Zürcher NR, She A, Bhanot A, Taillon BD, Schroeder FA, Wang C, Haggarty SJ, Hooker JM. Insights into neuroepigenetics through human histone deacetylase PET imaging. Sci Transl Med. 2016; 8(351): 351ra106. doi: 10.1126/scitranslmed.aaf7551.

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Updated at: 2023-08-02
Created at: 2023-08-01
Written by: Vesa Oikonen