The epigenetic control of gene expression has been shown to play a critical role in cancer initiation, progression, and resistance. Epigenetic regulation is most commonly controlled by a number of chemical modifications that alter the way DNA is packed, which in turn makes those genes easier to turn on or off. This natural pattern of activation, which is influenced by fetal environment, stress, diet, exercise and toxic exposure, among other things, is unique to each person. The three main types of epigenetic changes occur during epigenetic remodeling:
There are numerous enzymes which are related to epigenetic remodeling. Histone deacetylases (HDAC) are a class of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone. Its action is opposite to that of histone acetyltransferase. Histone deacetylases (HDACs) can regulate expression of tumor suppressor genes and activities of transcriptional factors involved in both cancer initiation and progression through alteration of either DNA or the structural components of chromatin. Protein acetylation is a reversible process regulated by histone deacetylases (HDAC) that is often altered in human cancers.
HDAC family: What are the cancer relevant targets?
Role for histone deacetylase 1 in human tumor cell proliferation.
Histone acetylation and the cell-cycle in cancer.
The role of histone deacetylases in prostate cancer.
Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer.
Thus, agents that modify the epigenetic environment of tumors will likely be an important addition to the anticancer arsenal. Recently, the role of gene repression through modulation such as acetylation in cancer patients has been clinically validated with several inhibitors of Histone deacetylases (HDACs).
HDAC inhibitors (HDACi) activate both the death-receptor and intrinsic apoptotic pathways. The death-receptor pathway is triggered by the ligation of death receptors, which results in binding of adaptor proteins (FADD) and the recruitment and activation of membrane-proximal activator caspases (caspase-8). These caspases in turn activate downstream effector caspases (caspase-3). The intrinsic apoptotic pathway is activated by internal stresses that induce mitochondrial membrane disruption mediated by pro-apoptotic proteins BAX and BAK. HDACi can induce the activation of the intrinsic apoptotic pathway. HDACi might still induce cell death in the absence of caspase activation after the production of reactive oxygen species (ROS).
HDAC inhibitors in cancer care.
Novel histone deacetylase inhibitors in clinical trials as anti-cancer agents.
Histone deacetylase inhibitors in cancer therapy.
Histone deacetylase inhibitors as anti-neoplastic agents.
Chronic lymphocytic leukemia (CLL) is one of four main types of leukemia. CLL is characterized by failure of mature lymphocytes to undergo apoptosis. CLL cells are inherently resistant to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). Histone deacetylase inhibitors (HDACi) enhance FADD (Fas-associated death domain protein) recruitment to TRAIL receptor (DR4) in the death-inducing signaling complex. Thus, enhanced FADD recruitment is a critical step in HDACi-mediated sensitization of CLL cells to TRAIL-induced apoptosis and this step is differentially affected by HDACi
Tumor cells up-regulate glycolysis but convert pyruvate into lactate instead of oxidizing it. Colon cancer cells silence the gene coding for LDH (lactate dehydrogenase)-B and up-regulate the gene coding for LDH-A, resulting in effective conversion of pyruvate into lactate. This is associated with markedly reduced levels of pyruvate in cancer cells compared with non-malignant cells. The silencing of LDH-B in cancer cells occurs via DNA methylation, with involvement of the DNA methyltransferases. Colon cancer is also associated with the expression of pyruvate kinase M2 (PK-M2), a splice variant with low catalytic activity. Pyruvate is a specific inhibitor of HDAC1 and HDAC3. Lactate has no effect on any of the HDACs.
HDACs regulate colon cell maturation and transformation and colon cancer cells exhibit increased HDAC activity compared with non-malignant cells. Pyruvate, but not lactate, is an inhibitor of histone deacetylases (HDAC) and an inducer of apoptosis in tumor cells and that SLC5A8 is obligatory for this process. Colon cancer cells silence SLC5A8, the gene coding for a Na(+)-coupled pyruvate transporter. This process is associated with an increase in intracellular levels of pyruvate, increase in the acetylation status of histone H4, and enhanced cell death. The following studies show that cancer cells effectively maintain low levels of pyruvate to prevent inhibition of HDAC1/HDAC3 and thereby to evade cell death. Tumor cells convert pyruvate into lactate as complementary mechanisms to avoid pyruvate-induced cell death.
HDACs and HDAC inhibitors in colon cancer.
SLC5A8 triggers tumor cell apoptosis through pyruvate-dependent inhibition of histone deacetylases.
Structural basis for tumor pyruvate kinase M2 allosteric regulation and catalysis.
