Targeting protein acetylation for improving cancer therapy.
Key words Calreticulin--histone acetyl transferases--histone deacetylases--histone deacetylase inhibitors--polyphenolic acetates
Past few decades have witnessed a great deal of research directed towards the development of approaches to improve the efficacy of conventional cancer treatment. The limitations of conventional therapy are resistance of tumour cells to therapeutic agents on the one hand and lack of specificity that causes deleterious effects to the normal cells/tissues on the other. Therefore, much of the efforts have been focused on the identification of molecular targets or the regulatory circuits that are specific only to cancer cells and govern processes like cell proliferation, differentiation and apoptosis. These regulatory circuits work either at the genetic level or at the protein level and any alterations in them not only dictates malignant growth, evasion of programmed cell death, sustained angiogenesis and metastasis but also confers resistance to therapy (1). The different regulatory circuits includes cell signaling networks, post-translational modification of proteins, chromatin remodeling and epigenomic gene regulation, etc'. Among the epigenome which is defined by DNA methylation patterns and the associated posttranslational modifications of histories and non histone proteins is the key regulatory circuit (2). The epigenome determines the chromatin remodeling and status of gene expression depending upon the intricate pattern of methylation and post-translational modification. The heritable alterations in chromatin structure by acetylation of histone and non histone proteins or DNA methylation patterns alter the expression of tumour suppressor genes or oncogenes associated with particular types of cancer (3). Acetylation of histones and non histone proteins contributes predominantly to this regulation by altering the chromatin structure and protein activity using acetyl CoA as the donor molecule. Several reviews have appeared in the recent past that elaborate on the aspects of protein acetylation. Therefore, a great deal of concern is given to this epigenomic gene regulation that is orchestrated both by acetylation and methylation in cancer (4). This review describes the different roles of acetylation involved in chromatin remodeling, gene expression, nucleocytoplasmic shuttling of proteins and also in the modification of cellular response to different DNA damaging agents that has a direct implication for the improvement of cancer therapy. A new acetyl CoA independent acetylation of proteins catalyzed by acetoxy drug: calreticulin transacetylase system is also described here and its role in modulating the cellular response similar to that of histone deacetylase (HDAC) inhibitors (Fig. 1).
Post-translational modification (PTM) of proteins
Post-translational (PTM) modification determines the structure and function of a protein and also maintains its native state. It is primarily responsible for the regulation of gene expression and the dynamic interplay between different signal transduction pathways. Major post-translational modifications like phosphorylation, acetylation, ribosylation, methylation, farnesylation, etc., create a docking surface with which the modules of other proteins and segments of DNA interact. These modifications are brought about by different enzymes that recruit different substrates like kinases use ATP for phosporylation; acetylases use acetyl CoA for acetylation, etc. These post-translational modifications are tightly regulated and balanced by another set of enzymes that remove these modifications thereby maintaining the equilibrium and cellular homeostasis (5). Further, there is a dynamic relationship between each of the post-translational modification in which one regulates the other. For example, serine phosphorylation regulates lysine acetylation of p53 during DNA damage (6). Loss of balance in any of these posttranslational modification results in indefinite signals for excessive proliferation resulting in cancer (7). Identification and clear understanding of this machinery, is therefore considered useful in designing the molecular targeted therapy enhancing the specificity for eliminating the malignantly transformed cells.
[FIGURE 1 OMITTED]
Phosphorylation is the best understood posttranslational modification. It is involved in the activation of many classes of proteins including the ones that regulate the cell cycle progression and damage response pathways. For example, phosphorylation of p53 inhibits the binding of Mdm2 (a ubiquitin ligase), increases p53 stability that results in tetramer formation and upregulation of p53 dependent gene expression thereby regulating damage response pathways including cell cycle arrest and apoptosis (8). On the other hand, phosphorylation of IkB [a nuclear factor kappa B (NFkB) inhibitor] in NFkB complex results in IkB dissociation and degradation thereby activating NFkB and translocating it to the nucleus that upregulates the expression of various prosurvival genes (9). A number of kinase inhibitors have been developed that disrupt the cell signaling by modifying the activation of proteins by the respective kinases. For example, LY 294002 and wortmannin (10) are two most widely used inhibitor of PI3K and IL-6-hydroxymethyl-chrol-inositol 2-2-O methyl, while AG957 inhibits the protein kinase B, Akt (11). These inhibitors decrease the cancer cell survival and are at a different phases of preclinical and clinical trials. DNA methylation recruits various repressor proteins and downregulates the gene expression (12). While ADP ribosylation of histone Hl opens chromatin structure (13).
Acetylation as post-translational modification
In the past decade, knowledge about acetylation has exploded, with targets rapidly expanding from histones to transcription factors and other nuclear proteins, and then to cytoskeleton, metabolic enzymes, and signaling regulators in the cytoplasm. Thus, protein lysine acetylation has emerged as a major post-translational modification as compared to phosphorylation. Acetylation can have multiple effects, including changes in protein-DNA interactions (14) or protein-protein interactions (15) (Fig. 2). The side chain of lysine residues is also targeted by another post-translational modification, ubiquitination. Polyubiquitination modulates protein function by inducing proteasome-dependent degradation. Protein acetylation can also affect protein stability, because it has been demonstrated that there is an active competition between acetylation and ubiquitination for the same lysine residues (16-18). Moreover, this modification has been extended to many regulators of DNA repair, recombination and replication; viral proteins; classical metabolic enzymes, such as bacterial and mammalian acetyl-CoA synthases; and recently to kinases, phosphatases and other signaling regulators (19). A decade ago, histone acetyl transferases (HATs) were first reported to acetylate the tumour suppressor p53, leading to the notion that HATs and HDACs are not just for histones. After that, various transcription factors like E2F, YY1, NF[kappa]B, SREBP, Smad7, etc. have been shown to be subjected to [epsilon]-amino lysine acetylation (20, 21). In vitro studies indicate that the N-terminal phosphorylation events in p53 may facilitate C-terminal acetylation on K382 by p300 a known histone acetyl transferase or on K320 by another histone acetyl transferase PCAF thus enhancing the sequence specific DNA binding activity. Acetylation and phosphorylation specific antibodies reveal that S33 and S37 are phosphorylated after UV or IR, a long, with acetylation at K382 in vivo, while p53 is also acetylated at K320 after UV exposure (22). These modifications appear to influence both the association of p53 with regulatory proteins and its ability to regulate the transcription of target genes. Moreover, acetylation of other crucial transcription factors like E2F, GATA1 at sites adjacent to DNA binding domain enhances the transcriptional activity whereas acetylation at sites within the DNA binding domain disrupts the DNA binding, e.g., HMG1. Acetylation also regulates the protein-protein interactions, for example, binding of transcriptional factors to co-activators (23). It also contributes to protein stability like E2F1 and [alpha] tubulin has longer half life on acetylation (24,25). Acetylation is also responsible for the nucleocytoplasmic shuttling and nuclear duration of various transcriptional factors thereby regulating the gene expression, for example, duration of nuclear NF-kB action is regulated by reversible acetylation (26). Therefore, acetylation of these transcription factors may have three functional consequences on their activity: increased DNA-binding ability, activation potential and protein half life. In addition, it was recently shown that p300/CBP-mediated p53 acetylation is commonly induced by p53 activating agents and inhibited by MDM2 (27). Similarly, as acetylation regulates the protein activity HDAC mediated deacetylation of transcription factors like E2F, Smad7, SREBP, and c-Myc promotes the ubiquitination and further proteasome mediated degradation of these proteins (28). Thus, HDAC-mediated deacetylation may be a novel mechanism to regulate the ubiquitination and degradation of some acetylated proteins. It is an interesting possibility that the stability of other proteins is also regulated by the balance between acetylation, deacetylation, and ubiquitination.
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Acetylation of histones and chromatin remodeling
Nucleic acids are the storage of genetic information and this information has to be accessible and inherited. The regulation of gene expression and the replication of the genome are central mechanisms to provide a 'translation' of the genetic blueprint into the machinery of life--the proteins. DNA packaged into nucleosomes is compacted as much as ten to twenty thousand folds from its naked state, and this topological complexity poses a significant obstacle to DNA templated processes such as transcription, replication, repair and recombination. Importantly, the structure of chromatin is dynamically regulated permitting localized decondensation and remodeling that facilitates the progress of nuclear machinery (29). Chromatin remodeling is an essential prerequisite that makes the genome accessible for gene expression and replication and acetylation plays an important role in it. The fundamental unit of chromatin is the nucleosome body that is an octameric assembly of basic proteins, the histones wrapped around by 146 bp of DNA. The histone that forms the nucleosome core complex is an octamer formed by H2A, H2B, H3 and H4 while histone H1 is the linker histone that links the two nucleosomes. Each core histone is composed of a globular domain and an unstructured N-terminal tail of 25-40 residues. The positively charged lysines of histone are bonded to negatively charged DNA thereby making the DNA template inaccessible to various transcriptional factors. Acetylation of the e amino lysines weakens the electrostatic attraction for the (negatively charged) nucleic acids and disassembles the nucleosomal histones, further the DNA sequence is accessible for various transcriptional factors and activates the gene transcription whereas deacetylation results in chromatin condensation and gene repression (30,31). The major point of interest lies in elucidating the mechanism involved in acetylation mediated gene regulation and the complex machinery that orchestrates this regulation, as it can be useful in identifying molecular targets for developing effective therapy.
According to histone code hypothesis, histone acetylation that occurs mostly at the e amino lysine residues creates an intricate pattern that constitutes a docking surface with which the modules of other proteins interact. Initial idea of docking surface comes from histone acetylation as histone acetyl transferases interact with higher affinity to peptides (32). Dynamic control of protein acetylation levels in vivo occurs through the opposing actions of histone acetyltransferases and histone deacetylases. HATs and HDACs continuously add and remove acetyl groups to specific lysine residues in the termini of the core histones and generate a dynamic steady-state level of acetylation (33,34). This dynamic state is perturbed and the acetylation levels of specific lysines at distinct chromatin sites are changed by external and internal cellular events that change the cellular transcription profile such as the equilibrium between the activities that continuously modify and demodify histone tails, can be perturbed by structural proteins such as HMGN1 (35). HATs and HDACs are well characterized (36,37). While their role in tumourigenesis has been widely studied, deacetylation has also been the target for developing cancer therapeutics recently. Several studies have also examined their role as modifiers of radiotherapy and chemotherapy.
Histone acetyl transferases (HAT)
The most well studied chromatin modifying complexes are the HAT complexes (38) The HAT proteins may function in multiple complexes and are classified as: (i) GNAT superfamily (Gcn5 related N acetyl transrerase), (ii) PCAF, (iii) MYST family, p300/CBP, nuclear receptor co-activators. The members of GNAT family include Gcn5 and its distantly related proteins Hap2 and Elp3 among which Gcn5 is the most studied one. Gcn5 contains a C-terminal bromodomain, an Ada2 interaction domain and a HAT domain (39). It is found to acetylate H3 (lys14) strongly and H4 (lys 8 and 16) weakly in a free histone mixture and is found to be highly conserved throughout the eukaryotes (40). The members of MYST family includes Ybf2/SaS3 (something about silence), Sas2 and Tip60 (Tat interacting protein) MOZ (monocytic leukemia zinc finger protein) and MORF (MOZ related factor) (41). MOZ is related to the cause of acute myeloid leukaemia, which results from the fusion between MOZ and CBP leading to aberrant chromatin acetylation and leukemogenesis. P300 and its close homologue CBP (CREB binding protein) along with PCAF, Gcn5, nuclear receptor co-activators and oncoprotein activator as cFos and cjun forms the transcriptional regulatory complexes with multiple acetyl transferase activities (42). P300/CBP co-activator is involved in wide variety of cellular processes including cell cycle control, differentiation and apoptosis and is associated with cancer and other human processes. It is a large protein of about 300KDa and more than 2400 residues with at least four interaction domains. It has a bromodomain as found in other HATs like Gcn5 and PCAF. Uniquely, p300/ CBP can acetylate all the four histones and this HAT activity is regulated by other factors such as viral protein E1A and regulatory protein TWIST (43,44) that binds to p300 and inhibits the HAT activity but has a HAT stimulatory effect on CBR The substrate of p300/ CBP other than histones are HMG1, activators p53, GATA-1, erythroyid druppel like factor, HIV Tat, a nuclear receptor co-activator, etc. Therefore p300/CBP is one of the most versatile acetytransferases, regulating the various key processes of cells. Recently, striking advances in the field indicate that HATs play a much larger role in transcription than previously believed. Moreover, recent data reveal that HATs also play important functions in transcriptional elongation. The conserved HAT protein Elp3 (elongator protein 3) is a subunit of the elongator complex, a component of RNA pol II. Eip3 in vitro can acetylate the four core histones indicating that HAT activity may be involved in the elongation process. Newer evidences reveal a role for HATs in additional cellular processes beyond transcriptional initiation. Also data indicate that HATs play an active role in DNA repair, revealing that modifiers may play an important part in any chromatin templated process.
Histone deacetylases (HDAC)
Acetylation of histone and non histone chromosomal proteins by HATs leads to decondensation of the chromatin. Chromatin remodeling and gene expression is simultaneously regulated by HDACs that condenses the chromatin structure by deacetylating histones. The HDACs have been classified into protein families that include classical HDACI family (HDAC 1, 2, 3 and 8), HDAC II family (HDAC 4, 5,6,7,9 and 10) and NAD+ dependent HDACs the SiR2 family. HDACs are the repressors of gene expression and known to operate with the repressor complex and not alone. Besides histones HDACs deacetylate different nuclear transcriptional factors and proteins like CDK 1 that are involved in cellular proliferation, differentiation and apoptosis (45). HDACs are well known to be associated with human oncogenesis as HDACs are known to suppress the expression of various tumour suppressor proteins and associated with well characterized cellular oncogenes (Rb and mad) leading to excessive proliferation and tumourogenesis (46,47). In acute promyelocytic leukaemia oncoprotein produced by fusion of the PML gene and retinoic acid receptor a gene appears to suppress transcription by the recruitment of HDACs (48). In addition, it was shown that HDAC 1 interacts with the ubiquitin ligase MDM2 and that HDACi-mediated deacetylation of the tumour suppressor p53 promotes MDM2-mediated ubiquitination and degradation of p53 (49). Thus, HDAC-mediated deacetylation may be a novel mechanism to regulate the ubiquitination and degradation of some acetylated proteins. The HDACs are also known to be involved in epigenetic gene silencing as in case of X chromosome inactivation. The methylated CpG islands will result in the recruitment of HDACs and thus repression of gene transcription (50).
Role of histone acetylation and regulation of gene expression is best illustrated by the use of HDAC inhibitors that creates the hyperacetylation condition and alters gene expression (51). A wide range of structures inhibit activity of class I/II HDAC enzymes, and with a few exceptions these can be divided into classes including (i) carboxylates (short chain fatty acids), (ii) small-molecule hydroxamates, (iii) electrophilic ketones (epoxides), (iv) cyclic peptides, (v) benzamides and (vi) other hybrid compounds. HDAC inhibitors have shown promise as cancer therapeutic as they are known to induce cell cycle arrest, cellular differentiation and apoptosis (52). Several HDAC inhibitors have exhibited potent antitumour activity in human xenograft models, suggesting their usefulness as novel cancer therapeutic agents. Several are currently in phase I/II clinical trials both in haematological malignancies and in solid tumours (45,53). Among these, trichostatin A is the most widely described one which is an antifungal agent that inhibits HDACs by binding to the zinc ion present at the catalytic pocket and is an irreversible inhibitor (54). Trichostatin A (TSA) blocks proliferation and triggers apoptosis in hepatocellular carcinoma cells, blocks cell cycle progression in HeLa cells and differentiation in ovarian cancer cells by changing p21 tumour suppressor gene and DNA binding Idl protein. TSA has also been shown to suppress growth of pancreatic adenocarcinoma cells and ACHN renal cell carcinoma via cell cycle arrest in association with p27 (55-57). It is relatively unstable and due to its toxicity and non specificity search for other compounds is undergoing. Suberoylanilide hydrozamic acid (SAHA) is a secondgeneration polar-planar compound (58-60) that has been shown to induce growth arrest, differentiation and/or apoptosis in hematopoitic cells and breast cancer cells (61,62). SAHA is currently under clinical investigation in both hematological and nonhematological malignancies (63,64).
HDAC inhibitors as modifiers of damage response pathways
Several studies have shown a relationship between chromatin structure and the DNA damage response pathways that includes activation of various signal transduction pathways, cell cycle progression, apoptosis and the DNA repair machinery. Since HDAC inhibitor interferes in chromatin remodeling by stabilizing the chromatin in an open state, it might upregulate genes responsible for apoptosis, cell cycle arrest and cellular differentiation (Fig. 3). Indeed, butyrate, an inhibitor of HDAC activity, has been reported to enhance radiation injury in human colon tumour cells and to increase radiation sensitivity of V79 chinese hamster lung fibroblast (66). Other studies have correlated chromatin compaction induced by trichostatin A, a HDAC inhibitor in irradiated cells with the extent of radiosensitization (67). HDAC inhibitors have also been shown to enhance the sensitivity of tumour cells to various therapeutic agents such as etoposide, cisplatin, doxorubicin, camptothecin, etc. as these inhibitors increase the accessibility of DNA to these drugs (67). SAHA has also been shown to enhance the efficacy of various cytotoxic agents such as tazotere, trastuzumab, gemcitabine and epothilone B in breast cancer, whereas the combination of 5-fluorouracil and other chemotherapy agents with phenyl butyrate also enhanced the cytotoxic effects in colorectal cancer cells (68-70). Therefore the hyperacetylation condition induced by these histone deacetylase inhibitors enhances the therapeutic efficacy of the conventional treatments.
Acetyl CoA independent aeetylation
Acetylation of proteins by histone acetyl transferases uses acetyl CoA as acetyl group donor molecule and is the most widely studied acetylation system, while little knowledge is available on acetyl CoA independent acetylation of proteins, although asprin mediated acetylation of cyclo-oxygenase is known for a long time (71). Recently, existence of a novel enzymatic acetylation system catalyzed by calreticulin an endoplasmic reticulum(ER) resident protein, has been reported, that acetylates target protein by using polyphenolic acetates as the acetyl group donor molecule. Although, calreticulin has been found to acetylate proteins using acetyl CoA, the efficiency appears to be very much lesser compared to the polyphenolic acetates as acetyl group donor molecule. Using a series of polyphenolic acetates with varying number of acetyl groups it has been demonstrated that 7, 8, di acetoxy, 4 methyl coumarin (DAMC) is the model acetylated polyphenol that has the highest degree of acetyl group transferring capability as compared to other polyphenolic acetates like 7-acetoxy 4 methyl coumarin (7-AMC) and 3- acetoxy- 4- methyl coumarin (3-AMC) (72). Recent reports describe that transacetylase purified from microsomal bodies of human placenta is identical to calreticulin (73). Modifications of the activities of a number of enzymes like cyto-P-450, NADPH- cyto c reductase, glutathione S transferase and nitric oxide synthase have been reported by this actetoxy drug: protein transacetylase acetylation system (TAase system). The sites of acetylation of glutathione-S-transferase analysed by MALDI TOFMS and LC\MS\MS are Lys-51, -82,- 124,- 181,- 191 and 210 and the N-terminal proline (74,75). The acetylation of eNOS by acetoxy drug:protein transacetylase system has been shown to increase eNOS activity in platelets leading to enhanced NO production and ADP-induced platelet aggregation (76). Therefore it appears that calreticulin can acetylate proteins using both acetyl Co A and polyphenolic acetates and qualifies some of the properties of type B acetyl transferases (77). In vivo studies suggest that the clastogenic effects of AFB1 in rat lung and bone marrow cells are significantly reduced by 7,8, di-acetoxy, 4-methyl coumarin (DAMC) (78). Since polyphenols are well known antioxidant compounds, which under certain conditions show pro-oxidant activity and generate oxidative stress in the cells (79), the polyphenolic acetates have been investigated for their cytotoxic effects related to oxidative stress. Polyphenolic acetates DAMC and quercitin penta acetates (QPA) have indeed shown a higher toxicity compared to their parental compounds in a breast carcinoma cell line (MDA-MB-468),which could be partly attributed to the oxidative stress generated (80), suggesting thereby that the acetyl groups also contribute to the cytotoxic effects. More recently a good correlation between the extent of inhibition of cell proliferation and the number of acetyl groups [DAMC, 7-acetoxy 4 methyl coumarin (MAMC)] observed in human brain glioma and carcinoma cell lines have lent support to the proposition that the polyphenolic acetates dependent protein acetylation has indeed a role in cell function. While the acetylation of proteins by this new acetoxy: drug protein transacetylase system is well understood in the in vitro system, elucidation of its specific role in the regulation of various cell functions in the cells needs further studies since the levels of calreticulin are upregulated in cancer cell besides alterations. Also, acetylated polyphenols inhibits cellular proliferation depending upon the number of acetyl groups attached to the parental molecule as DAMC is more toxic than MAMC as determined by different cytotoxic parameters (Verma A et al, unpublished observation). Acetylation of proteins by this new acetoxy drug: protein transacetylase system is well understood in the in vitro system but its establishment in the in vivo system still remains for its implication in cancer therapy.
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Conclusion and perspective
Acetylation of proteins by HAT/HDAC system using acetyl CoA is among the most widely studied posttranslational modification and plays an important role in determining cellular responses to variety of damage causing agents. Role of HDACs in tumour progression has been very well known and are regarded as a potential targets for developing effective therapeutics. HDAC inhibitors that create a hyperacetylation condition in the tumour cells promote cell cycle arrest, apoptosis and cellular differentiation and are implicated in cancer therapy. Calreticulin mediated acetylation system that uses polyphenolic acetates and acetyl CoA as acetyl group donating molecules demonstrated recently adds a new dimension to the acetylation dependent regulation of cellular responses to induced stress, which can be used to enhance the therapeutic gain.
Received December 27, 2007
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B.S. Dwarakanath, Amit Verma, A.N. Bhatt, V.S. Parmar ** & H.G. Raj *
Institute of Nuclear Medicine & Allied Sciences, * V.P. Chest Institute, University of Delhi, & ** Department of Chemistry, University of Delhi, Delhi, India
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|Author:||Dwarakanath, B.S.; Verma, Amit; Bhatt, A.N.; Parmar, V.S.; Raj, H.G.|
|Publication:||Indian Journal of Medical Research|
|Article Type:||Clinical report|
|Date:||Jul 1, 2008|
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