The combined anti-tumor effect of olaparib and SAHA was also observed in a Sorry, there is no online preview for this file type. . Synergistic Loss of Prostate Cancer Cell Viability by Coinhibition of HDAC and PARP. KB. Sorry, there is no online preview for this file type. Epigenetic Regulation by Androgen Receptor in Prostate Cancer. Article. A panel of human prostate cancer cells with graded castration resistant phenotype The disregulation of functional cooperation between HDAC-6 with hsp90, on one hand, Sorry, there is no online preview for this file type.
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Epigenetic modifications play a key role in the patho-physiology of prostate cancer. Histone deacetylases HDACs play major roles in prostate cancer progression. HDACs are part of a transcriptional co-repressor complex that influences various tumor suppressor genes. The combined use of HDAC inhibitors with other chemotherapeutic agents or radiotherapy in cancer treatment has shown promising results.
Various HDAC inhibitors are in different stages of clinical trials. In this review we discuss the molecular mechanism s through which HDACs influence prostate cancer progression, and the potential roles of HDAC inhibitors in prostate cancer prevention and therapy. Aberrant gene functions and altered patterns of gene expression play important roles in the biology of cancer. This deregulation is often governed at the epigenetic level i. Epigenetic silencing of the gene is very important in eukaryotic organisms, particularly in differentiation, development and imprinting.
However, deregulation of this silencing can result in the development of various human diseases, including cancer. The key hfac that are responsible fkletype epigenetic gene silencing are DNA methylation, modification of chromatin covalent modification of core histonesnucleosome positioning physical alteration and non-coding RNAs.
It is well established that methylation of cytosine in CpG islands results in gene silencing, and there is no doubt that this methylation is intimately associated with the development of cancer. Further, it has been demonstrated and well established that promoter methylation at CpG island sites prostatw to gene silencing. Init was shown that methylated DNA binding protein could bind methylated cytosine and makes a complex with histone deacetylase HDAC that lead to chromatin compactions and gene silencing.
Several detailed and informative reviews of the associations between DNA methylation and prostate cancer are available. Histone modifications, particularly acetylation and deacetylation, are the major driving force for epigenetic gene regulation.
The histone deacetylases are a group of enzymes that primarily target histone proteins; however, more than 50 non-histone targets of HDACs have been discovered. Elevated HDACs level in cancers results in increased proliferation of cancer cells, associated with down regulation of apoptosis, altered cell cycle regulation, enhanced tumor angiogenesis, and induction of various oncogenes.
As the organization and packaging of eukaryotic DNA is achieved through the addition of core histones H2A, H2B, H3 and H4, which form a complex structure called chromatin, the modification of core histones is of fundamental importance to conformational changes in chromatin. Chromatin acetylation correlates with transcriptional activity euchromatinwhereas deacetylation correlates with gene silencing. HDACs are also involved postate the reversible acetylation of non-histone proteins.
In mammals, total 18 HDACs have been identified and grouped into four classes i. Despite the important roles played by both HDAC class -I and -II enzymes in the regulation of gene expression, the exact mechanisms of their flletype activities are still not completely known. The zinc-coordinated active site activates an H 2 O molecule for hydrolysis of the acetyl group to form acetate.
The acetylation of lysine amino acids in core histones provides a balance of positive-negative charges that leads to chromatin relaxation. However, HDACs alter this balance; the resultant condensation of chromatin leads to gene silencing. Histone deacetylases work in multi-subunit transcriptional co-repressor complexes that are recruited by sequence-specific transcription factors to promoter regions.
The Role of Histone Deacetylases in Prostate Cancer
Deacetylation of sequence-specific transcription factors can decrease their DNA binding activity, and subsequently may repress transcription. Histones are proteins that form a scaffold around which a cell’s DNA is wrapped. Modification of these histone proteins by acetylation controls the tightness of the DNA around the histone proteins and, consequently, controls the expression of the genes.
In cancer, increased HDAC expression results in deacetylation of histone proteins. Deacetylation causes the DNA to be wrapped too tightly around the histones, thereby inhibiting gene expression.
Cancer may result if the genes affected are tumor suppressor genes. Over expression of HDACs in many cancer cells, results in repression of important growth suppressive genes, is an important mechanism to promote cancer cell proliferation.
However, some cancer cells over expresses a particular HDAC enzyme, for example, HDAC1 is over expressed in prostate cancer cells 47 and HDAC2 is commonly over expressed colorectal carcinomas, cervical dysplasias, endometrial stromal sarcomas and by gastric carcinomas.
Knockdown of HDAC1 or overexpression of cystatin reduces cellular invasion. Overexpression of HDAC1 has been reported in prostate and gastric cancers. Possible links between germ-line mutations in various HDACs and increased risk of lung and breast cancer have been investigated, but no associations have been observed. Prostate cancer is the second most frequently diagnosed cancer, and the third most common cause of cancer-related death in men in the United States and other developed nations.
Hypermethylation of CpG islands and chromatin remodeling play important roles in repression of various tumor suppressor genes during malignant transformation of prostate epithelial cells. The molecular mechanisms by which androgen antagonists inhibit prostate cancer cell proliferation are not fully defined. The acetylation of AR is necessary for co-activator bonding to AR as well as reduced co-repressor binding that promotes aberrant cell growth.
The ErbB3 binding protein, Ebp1 inhibits the proliferation and induces the differentiation of human ErbB-positive prostate cancer cell lines.
Ebp1 binds the tumor suppressor retinoblastoma protein Rb both in vivo and in vitroand Rb and Ebp1 cooperate to inhibit the transcription of the E2F1-regulated cyclin E promoter. Zhang and co-workers reported that Ebp1 can inhibit the transcription of other E2F-regulated reporter genes and of several endogenous E2F-regulated genes important in cell cycle progression in both Rb positive and negative cells.
ErbB blockade in conjunction with HDAC inhibition inhibits cell proliferation and induces apoptosis in prostate cancer cells. Maspin, a tumor-suppressor, is associated with cancers that are better differentiated, more sensitive to drug therapy, and prognostically more favorable.
Maspin interacts with HDAC1 in human prostate cancer cell lines and prostate tissues. This protein complex negatively regulates Ras mediated signaling and exhibits growth inhibitory effects on prostate cancer. It has been established that histone deacetylases are upregulated in most human cancers.
All HDAC isoforms screened were present in prostate cancer cell lines at various levels. HDAC1 protein was abundantly present in normal and malignant epithelial nuclei in prostate tissue, with lower expression in the stromal cells.
HDAC5 was absent in prostate tissues and HDAC8 was not detected in epithelial cells but was uniquely expressed in the cytoplasm of the stromal cells. However, more mechanistic studies are hdxc to explore the patho-physiology of histone deacetylases in prostate cancer. Weichert and co-workers investigated the expression of class I histone deacetylases by immunohistochemistry in prostate cancer samples.
HDAC1 immunohistochemical expression in prostate neoplasms was shown to proztate increased in pre malignant and malignant lesions and in hormone-refractory cancers. Further studies will be needed to explore the molecular link between mitochondria, HDAC and apoptosis.
HDAC activity is enhanced in various cancers including prostate cancer. Inhibitors of HDACs have emerged as potent anti-cancer agents. HDAC inhibitors cause the accumulation of acetylated histones, leading to activation of transcription of selected genes whose expression causes inhibition of tumor cell growth and induction of apoptosis.
Some newly synthesized compounds are potentially effective for both cancer ciletype and cancer therapy. Various HDAC inhibitors with putative radio-sensitization properties have been screened. Relatively little is known about the molecular mechanisms of HDAC inhibitors and their modes of action.
Five classes of HDAC inhibitors have been characterized:. The response of prostate cancer cells to HDAC inhibitors is not uniform, but cell line, target and inhibitor specific 97 as shown in Table There are a number of reports pertaining to the utility of various HDAC inhibitors in the management of prostate cancer.
The detail description of HDAC inhibitors in context to prostate cancer is described below. SAHA is marketed under the name Vorinostat brand name Zolinza for the treatment of a skin cancer called cutaneous T cell lymphoma.
The Molecular Perspective: Histone Deacetylase — Goodsell 8 (4): — The Oncologist
Further they induce dissipation of the mitochondrial transmembrane potential, to activate caspase-3, and to trigger DNA fragmentation. Trichostatin A is an antifungal antibiotic that selectively inhibits the class I and II mammalian histone deacetylase enzymes, but do not inhibits class III Sirtuins.
TSA inhibits the eukaryotic cell cycle during the beginning of the growth stage. This down-regulation of phospho-Akt is not mediated through deactivation of upstream kinases or activation of downstream phosphatases.
However, the role of LBH in the inhibition of tumor angiogenesis has already been reported in mice model. R is a novel broad spectrum hydroxamate based HDAC inhibitor. Recently Hassig et al. Sodium butyrate is a four-carbon chain volatile fatty acid induces apoptosis in prostate cancer cells.
The Role of Histone Deacetylases in Prostate Cancer
FK is a bicyclic peptide containing a non-cysteine disulfide bridge, isolated from Chromobacterium violaceum Strain WB It has potential anticancer activity in vitro and showed significant inhibitory effects on the growth of human solid tumors xenografts. Valproic acid is a potent HDAC inhibitor that is able to check cell proliferation, upregulates the androgen receptor levels and E-cadherin expression in human prostate cancer cells.
However the effect of valproic acid is cell line specific as the effects are more pronounced in androgen independent PC-3 cells than prostatr dependent LNCaP. Various in-vitroin-vivo and clinical data suggest that cancerous cells undergo a transdifferentiation process to fioetype NE-like cells.
Furthermore, VPA can modulate the expression of different androgen metabolism genes and may enhance dihydrotestosterone DHT catabolism. It is a phenylbutyrate-derived histone deacetylase inhibitor induces apoptosis and down regulates phospho-Akt, Bcl-xL, and survivin level as well as suppresses the growth of PC-3 tumor xenografts. MS exerts growth arrest and induces cell death in prosttate cancer cell lines as well as inhibits the growth of subcutaneous xenografts.
The isothiocyanates are the constituents of cruciferous vegetables and have anticancer properties. SFN is an isothiocyanate from broccoli having chemopreventive properties. SFN induces cell cycle arrest and activation of apoptosis in benign prostate hyperplasia, androgen-dependent prostate cancer and androgen-independent prostate cancer cells. Several clinical trials with HDAC inhibitors are currently undergoing in combination with retinoids, taxol, gemcitabine and with radiation therapy in patients with hematologic malignancies and solid tumors including those of lungs, breast, bladder, breast and pancreas.
However there are no reports available on clinical trials with prostate cancer. Histones deacetylases are among the key regulators in the development and progression of diletype cancer. The functions of HDACs are diverse: At least 18 HDACs have been characterized and categorized into four different groups on the basis of domain organization and sequence identity. Various studies have shown that HDACs have specific targets, but the exact role of specific HDACs in the patho-physiology of prostate cancer are still not well understood and need further prosttate.
Furthermore, HDAC inhibitors are emerging as promising drugs for cancer therapy and various inhibitors are undergoing clinical trials. The molecular mechanisms and targets of most HDAC inhibitors have not been elucidated.
Preclinical studies of combination therapies, using HDAC inhibitors with other anti-cancer agents, have shown promising results that justify further investigation for potential use in the therapy of prostate cancer. Although normal cells appear to be relatively resistant to the effects of HDAC inhibitors as compared to transformed cells, the pharmacological safety profiles of various HDAC inhibitors are not currently established. The efficacy and usefulness of isoform-specific versus broad spectrum HDAC inhibitors are under debate.
In various in-vitro studies of HDAC inhibitors, untreated cancerous cell lines have been used as controls, but ideally their corresponding normal cell lines should also be evaluated in such experiments.