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Review
. 2012 Feb 2;31(5):537-51.
doi: 10.1038/onc.2011.267. Epub 2011 Jul 4.

Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy

S Spiegel  1 , S Milstien, S Grant
Affiliations
Review

Endogenous modulators and pharmacological inhibitors of histone deacetylases in cancer therapy

S Spiegel et al. Oncogene. .

Abstract

The class-I histone deacetylases (HDACs) HDAC1 and HDAC2 belong to a family of 11 zinc-dependent human HDACs and are overexpressed in many cancers. Inhibitors of these HDACs now in clinical trials show activity against several types of cancers. This review is focused on recent advances in both clinical and preclinical efforts to understand the basis for the actions of HDACis, with emphasis on implications for rational combinations with conventional or other targeted agents. We will address new perspectives on the molecular mechanisms by which HDACs act and how these actions relate to cancer. We will also review new evidence showing that HDACs are direct intracellular targets of the potent sphingolipid mediator S1P, the first identified endogenous nuclear regulator of these enzymes, linking sphingolipid metabolism in the nucleus to remodeling of chromatin and epigenetic regulation of gene expression. Understanding how endogenous molecules regulate HDAC activity in vivo may facilitate the search for safer and more effective anticancer drugs capable of interfering with HDAC functions in a highly specific manner.

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Conflict of interest statement

Conflict of interest

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Human HDAC superfamily showing domain organization and cancer relevance
HDACs are grouped into different classes according to sequence similarity. Blue indicates the conserved catalytic domain; asterisks indicate nuclear localization signals; ZnF, zinc finger, myocyte enhancer factor-2 (MEF2)-binding motifs are depicted as short turquoise cylinders; and 14-3-3 chaperone binding motifs are shown as short yellow cylinders labeled with ‘S’ (for serine phosphorylation sites).
Figure 2
Figure 2. Epigenetic, non-epigenetic or indirect epigenetic effects of HDACis
HDACis, such as vorinostat, prevent histone deacetylations leading to transcription activation or repression. HDACis also can affect the acetylation status of transcription factors (E2F, NF-κB, Stats) and other proteins with important biological functions (α-tubulin, Ku70, Hsp90). See text for more detailed information.
Figure 3
Figure 3. HDACis induce “Inside out” signaling involving ATM/NEMO axis and NF-kB activation
HDACis, by inducing ROS and double strand DNA breaks, induce SUMOylation of NEMO and activate ATM. This leads to phosphorylation of NEMO by ATM and subsequent translocation of NEMO with ATM from the nucleus. NEMO is then capable of binding and activating the IKK complex culminating in NF-κB activation and expression of survival genes.
Figure 4
Figure 4. Inside out signaling by S1P
Binding of growth factors (e.g. EGF) to their tyrosine kinase receptors activates ERK1, which then phosphorylates cytosolic SphK1 leading to its translocation to the plasma membrane where its substrate sphingosine resides. In some cells, SphK2 is at the plasma membrane and can also be activated by ERK1 phosphorylation. Once produced, S1P can be exported out of cells by ABC transporters to activate cell surface S1P receptors in an autocrine or paracrine manner, known as “inside out signaling by S1P”. This leads to activation of mutiple signals downstream of G proteins important for tumorigenesis, including growth, survival, motility, invasion and regulation of gene expression. In many types of cancer cells, SphK2 is predominantly in the nucleus where it produces S1P that inhibits class I HDACs.
Figure 5
Figure 5. Role of S1P formed in the nucleus by SphK2 in regulation of histone acetylation and p21 expression
Activation of nuclear activation of SphK2 leads to formation of S1P, which inhibits HDAC1 and HDAC2, leading to increased histone acetylation p21 gene expression. In response to DNA damage (doxorubicin), p53 is upregulated, which leads to induction of BAX, NOXA, and PUMA (cell death mediators), and also induces p21, which suppresses apoptosis and induces cell cycle arrest. Downregulation of SphK2 prevents induction of p21 and removes p21-mediated protection against apoptosis, facilitating cell death.
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