Histone modifications: A review about the presence of this epigenetic phenomenon in carcinogenesis

Accepted Manuscript Title: Histone modifications: a review about the presence of this epigenetic phenomenon in carcinogenesis Authors: Emanuely Silva Chrun, Filipe Modolo, Filipe Ivan Daniel PII: DOI: Reference:

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Please cite this article as: Emanuely Silva Chrun, Filipe Modolo, Filipe Ivan Daniel, Histone modifications: a review about the presence of this epigenetic phenomenon in carcinogenesis, Pathology - Research and Practicehttp://dx.doi.org/10.1016/j.prp.2017.06.013 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Histone modifications: a review about the presence of this epigenetic phenomenon in carcinogenesis Emanuely Silva Chrun a, Filipe Modolo b, Filipe Ivan Daniel b,* a

DDS, MSc, PhD student of Post graduate program in Dentistry-Oral Diagnostic, Department of Pathology, Federal University of Santa Catarina, Florianopolis, Santa Catarina, Brazil. E-mail: [email protected] b DDS, PhD, Professor Department of Pathology, Federal University of Santa Catarina, Florianopolis, Santa Catarina, Brazil. E-mail: [email protected], [email protected]. * Correspondence may also be addressed to Filipe Ivan Daniel. Tel: +55 48 3721 3483; Fax: +55 48 3721 9473; Email: [email protected]

Abstract Among the epigenetic changes, histone acetylation has been recognized as a fundamental process that strongly affects gene expression regulation. Disrupt of this phenomenon has been linked to carcinogenesis. In this review, we analysed studies reporting the process of histone modification, the enzymes associated and affected genes concerning human malignancies and histone enzyme inhibitor drugs used in cancer treatment. Variable degrees of expression of HDACs (histone deacetylases) and HATs (histone acetyltransferases) are found in many human malignant tissues and the histones acetylation seems to influence different processes including the progression of cell cycle, the dynamics of chromosomes, DNA recombination, DNA repair and apoptosis. Thus, the control of aberrant activity and/or expression of these proteins have been favorable in treatment of diseases as cancer. HDACi have shown efficacy in clinical trials in solid and hematological malignancies. Therefore, the development and use of HDACs inhibitors are increasing, leading to continue studying these enzyme expressions and behavior, aiming to determine tumors that will respond better to this type of treatment. Keywords: Histone Deacetylases; ; ; , Histone Acetyltransferases, Genes, Review. Introduction Epigenetic is an interesting and relatively recent field in biology, referring to the regulation of gene expression, without alterations in DNA sequence and with a heritable pattern during cell division. Progress has been made in knowledge of epigenetic modifications in normal and diseased tissues ` [29, 111]. It is known that these modifications are reversible and play a key role in develop ment of some disorders[150]. Researches in epigenetics have provided new insights into some kinds of diseases, especially human malignancies, neurodevelopmental disorders (Alzheimer's, Parkinson's and Huntington's diseases, multiple sclerosis and epilepsy)[139] and autoimmune sickness (rheumatoid arthritis[59], type 1 diabetes[93] and lupus erythematosus[55]). Besides the already known genetic alterations, the epigenetic deregulation is of great importance in the development of malignant tumors[23] becoming an obvious focus of research in this field[94, 111]. The main types of epigenetic information are: a) DNA methylation where the addition of a methyl group to 5-carbon of cytosine in CpG islands[17] promotes gene silencing and also involves histone deacetylation through interaction with co-repressor complexes[102]; b) miRNAs[58, 75], small noncoding RNAs involved in the regulation of fundamental cellular processes and crucial to transcription and translation[36], which deregulation have been related to many human cancers pathogenesis[64]; and, c) histone modifications, characterized mainly by alterations in the acetylation status, also providing access or not of transcription factors to sequences of nucleotides.[22] This literature review aimed to analyze studies reporting the process of histone modification, the enzymes related and affected genes concerning human malignancies as well histone deacetylase inhibitors (HDACi) drugs already used for cancer treatment. Histones, histone modifications and related enzymes Histones are proteins that, together with DNA, comprises the nucleosome formed by the core histone octamer (two heterodimers of H2A and H2B along with two heterodimers of H3 and H4), which

is wrapped by two turns of 147-base-paired DNA strand[106], while the H1 protein establishes and maintains the higher-order chromatin structures[53]. Each histone comprising the octamer within the nucleosome is rich in lysine tails extending out of it and, therefore, the accessibility to the DNA in the nucleosome is, in part, controlled by modifications of these tails[130]. Histones may be submitted to several post-translational modifications as ribosylation, ubiquitynation and sumoylation of lysines, phosphorylation of serines and threonines, acetylation or methylation of lysines and arginines. Lysine residues in histone tails have a positive charge that interacts with the negatively charged phosphate backbone of DNA. Covalent modifications lead to alterations in chromatin structure and, thus, affect accessibility of transcription factors to ‘read’ and/or copy the nucleotide base sequences; therefore, these structures are dynamic and have capacity of folding (heterochromatin) and unfolding (euchromatin) regulation[106]. Histone deacetylases (HDACs) and histone acetyltransferases (HATs) are enzymes that influence DNA transcription through the balance between histone acetylation and deacetylation in normal cell function. Histone acetylation reduces chromatin condensation (Fig. 1): HATs catalyse the transference of an acetyl group (negatively charged) from acetyl-CoA to the amino-terminal tail of lysine, neutralizing the histone positive charge[12]. It generates slackness between DNA-histone and also between nucleosomes, allowing access of transcription factors and, therefore, DNA transcription. On the other hand, histone deacetylation returns to original condensation: HDACs remove acetyl group recovering the positive charge, permitting interactions between negatively charged DNA and histone protein, resulting in condensation of chromatin structure (Fig. 2), which is associated with gene repression[91, 94]. To date, 18 human HDACs have been identified and are classified into four classes[34, 78, 123]. Class I comprises HDAC1, HDAC2, HDAC3, and HDAC8, mainly located in the cell nucleus[38, 78]; Class II HDACs are located both in the nucleus and cytoplasm (HDAC4, 5, 7, and 9) or only in cytoplasm (HDAC6 and 10); Class IV includes HDAC11, which appears both in the nucleus and cytoplasm; while Class III is made up by Sirtuins which, different from the others histone deacetylases, are Zn-independent[78]. As HDAC1 and HDAC2 are inactive when produced by recombinant techniques, cofactors are necessary for its activity to occur. In vivo, its activity is triggered only within a complex of proteins related to HDACs[24]. Among them, the corepressor protein Sin3 is postulated to mediate protein-protein interactions in several regulatory systems of gene expression. As Sin3 does not display DNA binding domain, promoter targeting is achieved through interactions with other sequence-specific DNA-binding proteins, and therefore require HDACs as prosecutor of this link to achieve its repression function. MadMax complex is strongly induced during cell differentiation and acts suppressing cell proliferation, through the complex comprised with Sin3/HDAC[44] (Fig. 3a). Ume6, Ncor and YY1[76] (all transcription repressors) both request Sin3 that, in turn, needs HDACs to bind DNA. MeCP2 is one of the four main proteins with a methyl-CpG binding domain able to link to methylated DNA, resulting in transcriptional silencing probably due to Sin3/HDAC complex recruitment to achieve gene repression[9, 23] (Fig. 3b). Thus, HDACs indirectly or directly are requested by these other factors, enhancing its role and importance in gene silencing, showing to be fundamental for regulatory mechanisms governing cell proliferation and differentiation[39]. HATs have been organized in two general classes (A-type and B-type) based in their probable origin and function in cells. A-type, with nuclear localization, probably participates catalyzing the acetylation and events related to gene transcription. B-type HATs are likely responsible for catalyzing acetylation events related to the transport of newly synthesized histones from the cytoplasm to the nucleus and its deposition on the replicated DNA. HAT domains motif A contains binding sites to acetylCoA and are present in structure of all proteins classified as HAT activity[117]. In addition, based on its primary-structure, HATs are organized into families. The four HAT families most studied are: the GNAT family (Gcn5, PCAF, Hat1, Elp3, and Hpa2); the p300/CBP family (p300, and CBP); the MYST family (Esa1, MOF, Sas2, Sas3, MORF, Tip60, and Hbo1), and the Rtt109 [25, 117].

Many of HATs identified to date do not work isolated in vivo, and likewise HDACs, HATs often act within a coactivator complex. An in vitro study by immunoprecipitation test using antibody to recognize hyperacetylated histones noted that these histones are globally located in regions of DNase sensitivity which is a region transcriptionally active, reinforcing the role of HATs in transcription[117]. Each HAT exhibits site and histone specificity, and for each distinct physiological function specific histone acetylation at specific locations are needed. The specificity becomes wide within complexes[106]. Some of coactivators complexes most cited in studies are: ADA (Gnc5, Ada2, and Ada3), SAGA (SPT, ADA2B, ADA3, SGF29/STAF36, and GCN5/PCAF)[37, 95], STAGA (SPT3-TAF9GCN5[152]), and ATAC (Ada Two-A containing-GCN5, ADA2A, ADA3, and SGF29[143],37). GCN5 and PCAF are two paralogous yeast Gcn5-like acetyltransferases that influence diverse biological processes by acetylating histones and non-histone proteins, chromatin regulation, and gene-specific transcription as part of these multiprotein complexes[71, 143]. Within ADA and SAGA complexes, acetylation activity of Gcn5 is increased and modifies chromatin structure and regulation of the basal transcription machinery[115]. Direct interactions between histone modifying enzymes and DNA sequence-specific transcriptional regulators are crucial for achieving targeting histone modification[106]. Aberrant histone deacetylation is responsible for transcriptional repression of genes involved in negative regulation of cell differentiation and proliferation, migration and metastasis in human malignances[35]. The global histone modification levels are predictive of cancer recurrence and this indicates that histone acetylation/deacetylation is a versatile regulatory event which plays a key role in various cellular processes[124]. HDACs and HATs in cancer Although acetylation/deacetylation events are specific and well controlled processes in the normal cell, histone hipoacetylation plays an important role in cancer initiation by changing gene expression and cell phenotype[67]. Three situations are possible for its occurrence: HDACs overexpression and/or exceeded activity; decreased amount of HATs and/or its activity; and both conditions concomitantly[134]. The sequence of histone modifying enzyme action also affects the overall protein machinery: one modification leads or inhibits the other. The enzyme-substrate specificity (the specific residue of certain histone tail) is as important as the recruitment of the enzyme at the exact moment. These phenomena are associated with distinct chromatin status and, as previously discussed, alterations in chromatin status lead to changes in transcriptional process[106]. HDAC expression has been investigated in different human malignancies by several authors. In this review, we raised manuscripts about expression of HDACs (Class I, II, III and IV) in cancer tissues such as oral, breast, gastric, lung, prostate, colorectal, ovary, endometrial, pancreatic, thyroid, esophageal, leukemia, and lymphoma (Table 1). HDAC1 and HDAC2 are the deacetylases proteins most studied and well understood in human cancer and cell lines, with predominantly nuclear staining when conducting immunohistochemistry[1, 15, 42, 45, 51, 72, 73, 81, 98, 100, 121, 134, 135, 146]. Although increased expression was found in most investigations, some tumors (breast cancer[73, 98, 125] and leukemia[96]) showed inconstant or varied expression. Breast cancer and leukemia are the most investigated tissue by most authors. Breast cancer showed wide variation of HDAC1, HDAC2, and HDAC3 expression while these proteins are overexpressed in the other investigated malignancies. Leukemia[40, 96, 149] reports enhanced expression for most deacetylases types. Other authors found heterogeneous expressions within several hematologic malignancy subtypes. Abnormal expression of HDACs and HATs may cause epigenetic alterations associated with malignant cell behavior and has been associated with tumor development and progression[34, 145, 146]. Histone acetylation and deacetylation affect several gene expression involved in tumorigenesis. The HDACs may repress transcription of differentiation factors, allowing cell proliferation without differentiation, cyclin-dependent kinases inhibitors, and pro-apoptotic factors, not admitting the programmed cell death. This repression promotes the unregulated cell growth observed in the initiation and progression of malignant tumors[35]. All these events can be supported by evidence of studies that utilized HDAC inhibitors (Table 2).

The role of histone modification proteins in cancer is based on the following explanation: when there is overexpression of HDACs, probably activities of tumor suppressor genes such as p21 (cell cycle progression inhibitor) are silenced leading to tumor initiation and/or progression, even as other experiments show that deacetylation of p53 by HDACs is likely to be part of the mechanisms that control the physiological activity of p53 and depends on the p53 region acetylated by p300/CBP (HAT) [57]. It has also been suggested that loss of HDAC expression, together with the lack of control in oncogenes expression, might help tumorigenesis depending on the corepressor complex to which it binds, for example, Rb expression requires HDAC1 to repress transcription and plays a role on tumor suppressor[11, 84], the same process occurs with AML1-ETO (frequently altered in leukemias)[3]. Beyond HDAC expression changes in several types of human malignances, translocations, mutations and deletions in HAT and HAT-related genes may also contribute to global imbalance of histone acetylation[111]. With the acetylation it is suggested that the acetyl-lysine in histone tails provide recognition of the binding sites by factors involved in gene transcription[132]. The role of various types of HAT within the malignant tumors can be subject of extensive discussion, as there are evidences of its action collaborating with expression of classical tumor suppressor gene and, in turn activating oncogenes, depending on the studied target gene (Table 3). Thus, it is possible to suggest that genetic changes may lead to epigenetic changes. And this may also be the reason for the overexpression of HDACs, since some translocations result in overexpression of proto-oncogenes by removing its normal regulatory elements and keeping them under the control of a highly active promoter[74]. Thereby, histone modifying enzymes and complexes are involved in such diverse processes as transcription activation or gene silencing of key genes such as DNA repair and cell cycle regulatory genes. HDAC inhibitors (HDACi) HDACi are a group of drugs with different structures and biological activity and specificity shown to be potent antiproliferative agents, with relatively little effect on normal tissues and clinically welltolerated[63, 77]. These drugs overall exert their anticancer activity by favoring the acetylation and reversing the excess histone deacetylation leading to re-expression of silenced genes and contributing to reverse the malignant phenotype[97]. The effects of HDACi in gene transcription are complex. Among their properties are cell cycle arrest, generation of reactive oxygen species, apoptosis induction, and antiangiogenic effects. These cascades of changes in gene expression occur due to acetylation of histone and non-histone[97] nucleossomal proteins[114]. The effects in acetylation of the non-histone proteins can affect many vital regulatory process including gene transcriptional activation, resuming the production of proteins (i.e. p53, p21 and tubulin)[77]. Another important effect is that HDACi also act in cellular cycle checkpoints, allowing greater specificity for tumor cells, considering that checkpoints are often defective in cancer cells[144]. Essentially formed by zinc-binding domain, a terminal group, and a chain linker between them, synthetic HDACi are classified according to their distinct chemical structures in mainly four classes[28]: 

Hidroxamic acid-based (related to trichostatin A [TSA], from the Streptomyces hygroscopicus): vorinostat (SAHA), belinostat, abexinostat, pracinostat, resminostat, givinostat, panobinostat, and CUDC-101;  Benzamide derivatives: mocetinostat, entinostat and tacedinaline  Short chain fatty acid-based (related to sodium butirate): valproic acid and phenylbutyrate  Cyclic peptide: romidepsin Several inhibitors have been developed and are in clinical trials to date. HDACi have been tested in solid and hematological tumors showing good results. Nevertheless, a study by Haberland et al. (2009)[41] showed that systemic administration of HDACi, which can inhibit most or all HDACs ubiquitously expressed, is well tolerated in vivo and acts upon numerous disease-associated gene expression programs in an apparently specific manner. Thereby unexpectedly, normal cells are often less sensitive to HDACi than are tumor cells[41], which is very positive in terms of antineoplastic therapy. The use of inhibitors has been clinically validated in cancer patients by FDA (Food and Drug

Administration, USA) approval. Moreover, clinical trials of several HDACi for use as anticancer drugs alone or in combination with other therapeutic agents are in progress (Table 4). HATs and HDACs are recognized as fundamental in the process that affect strongly the regulation of gene expression. These structural and functional studies have supported efforts to elucidate the molecular characteristics, mechanisms and regulation of these enzymes. Such efforts are crucial to the development of these therapies that target histone-modifying enzymes within their specific complex. Conclusion Several studies have reported varying degrees of HDACs and HATs expression in many human malignant tissues and there is evidence that substrates of HDACs and HATs are not limited to histones, promoting a cascade of modifications with their deregulation. Considering the exact function of HAT and HDAC is unclear, including the suitable balance between them, future studies may clarify the function of these proteins, improving therapeutic strategies together with existing therapies. Although HDACi have shown efficacy in clinical trials in solid and hematological malignancies, some authors suggest that the use of HDACi should be directed to cases that strongly express HDACs in their tumor cells. Despite these divergences, development and use of HDACs inhibitors are increasing, leading us to continue studying these enzyme expressions and behavior, aiming to determine tumors that will respond better to this type of treatment. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conflict of Interest Statement Authors declare no conflict of interest. References

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FIGURES LEGENDS Fig. 1. HAT and HDAC action. Acetylation catalyzed by HAT affects transcription through neutralization of the positive charge of histones, weakens interactions between DNA and histone or among nucleosomes, thus reducing chromatin compaction and favoring gene transcription. In an opposite way, HDACs promote deacetylation returning it to chromatin compaction and transcriptional silencing. Fig. 2. Histone structure modifications mediated by HAT and HDAC. The figure shows lysine at histone N-terminal tails have lysines suffering acetylation (HAT action) and deacetylation (HDAC action). In cellular pH, of approximately 7.4, the amine group is positively charged. When catalyzed by HAT, an acetyl group is added to its structure and the positive charge is neutralized. On the other hand, when HDAC acts an opposite mechanism occurs. Fig. 3. Hypothesis illustration of corepressor complexes involving HDAC. (A) Mad-Max require Sin3AHDAC to promote transcriptional repression. (B) Methylated CpG sites attract methyl-binding proteins such as MeCP2 that, in turn, attract Sin3A and HDAC for silencing transcriptional machinery.

Figr-1

Figr-2

Figr-3

Table 1. Summary of HDACs expression in human malignances. Protein

Tissue

Sample

Oral

49 patients

Lip

30 patients 91 patients

Lynphoma

Breast

Method

IHC

Reference

↑

[25]

↑

[5]

↓

[14]

↑

[1]

104 patients

IHC/WB

↑

[15]

200 patients

IHC/RT-PCR

Heterogeneous

[13]

20 patients

IHC/WB

↑

[18]

58 patients

IHC

↓

[24]

238/300 patients

IHC

Heterogeneous

[17],[22]

8 patients/2 cell lines

IF/WB

283 TMA

↑

[26]

Heterogeneous

[16]

↑

[28]

qRT-PCR/WB

↑

[7]

25 patients

IB/RT-PCR

↑

[4]

20 patients

IHC/WB

↑

[18]

102 patients

IHC/RT-PCR

↑

[21]

20 patients

IHC/WB

↑

[18]

28 patients

IHC/RT-PCR

↑

[19]

14 patients

IHC/FC/IF/WB

↑

[8]

20 patients

IHC/WB

↑

[18]

192 patients

IHC

↑

[27]

64 patients

IHC

↑

[10]

20 patients

IHC/WB

↑

[18]

20 patients

IHC/WB

↑

[18]

115 patients

IHC

↑

[9]

17 patients

IHC

↓

[12]

41 patients

IHC

↑

[2]

20 patients

IHC/WB

↑

[18]

57 patients

IHC

↑

[11]

20 patients

IHC/WB

↑

[18]

74 patients

IHC

↑

[6]

Esophageal

20 patients

IHC/WB

↑

[18]

Oral

93 patients

Leukemia

Gastric HDAC1 Lung

Prostate

Colorectal Ovary Endometrial Pancreatic Thyroid

94 patients 39 patients 24 cell lines 93 patients

49 patients Lip Lymphoma

Breast

HDAC2 Leukemia

Gastric Lung Prostate Pancreatic Colorectal, ovary, pancreatic, thyroid and esophageal

qRT-PCR

IHC

Lymphoma

[3]

↑

[25]

↑

[5]

IHC

↑

[1],[14]

104 patients

IHC/WB

↑

[15]

20 patients 8 patients 2 cell lines 58 patients

IHC/WB

↑

[18]

IF/WB

↑

[26]

30 patients

IHC

↓

[24]

Heterogeneous

238/300 patients 94 patients 39 patients/24 cell lines 93 patients

qRT-PCR

↑

qRT-PCR/WB

↑

[17], [22] [16] [28] [7]

71 patients

IHC

↑

[23]

20 patients

IHC/WB

↑

[18]

20 patients

IHC/WB

↑

[18]

20 patients

IHC/WB

↑

[18]

192 patients

IHC

↑

[27]

57 patients

IHC

↑

[11]

20 patients

IHC/WB

↑

[18]

8 patients/2 cell lines

IF/WB

↑

[26]

238 patients

↑ IHC

300 patients 20 patients

HDAC3

↑

283/91 patients

283 TMA

IHC/WB

Heterogeneous

[1] [17] [22]

↓

[18]

↑

104 patients 94 patients 39 patients/24 cell lines 20 patients

qRT-PCR

↑

IHC/WB

↑

[15] [16] [28] [18]

20 patients

IHC/WB

↑

[18]

192 patients

IHC

↑

[27]

Colorectal, ovary, pancreatic, thyroid and esophageal Lymphoma

20 patients

IHC/WB

↑

[18]

91 patients

IHC

↑

[14]

Breast

8 patients 2 cell lines

IF/WB

↓

[26]

Leukemia Lung Prostate

HDAC4

Expression

Leukemia

Endometrial HDAC5

Lymphoma Breast Leukemia

qRT-PCR

Heterogeneous

[16]

39 patients/24 cell lines 93 patients

94 patients

qRT-PCR/WB

↑ ↑

[28] [7]

41 patients 91 patients

IHC IHC

↑ ↑

[2] [14]

8 patients 2 cell lines 94 patients

IF/WB

↓

[26]

qRT-PCR

Heterogeneous

[16]

↑

[28]

39 patients/24 cell lines HDAC6

Pancreatic Oral

57 patients 9 patients

IHC IHC/IF/WB/qRT-PCR

↑ ↑

[11] [20]

Lymphoma

91 patients

IHC

↑

[14]

Breast

58 patients

IHC

↑

[24]

Heterogeneous

[22]

300 patients 8 patients/2 cell lines

IF/WB

↑

[26]

94 patients 39 patients/24 cell lines 8 patients 2 cell lines 94 patients

qRT-PCR

↑

IF/WB

↓

[16] [28] [26]

qRT-PCR

↑

[16]

41 patients 20 patients

IHC IHC/WB

↑ ↓

[2] [18]

8 patients 2 cell lines 94 patients 39 patients/24 cell lines 93 patients

IF/WB

↑

[26]

qRT-PCR

↑

RT-PCR/WB

↑

[16] [28] [7]

Gastric, lung, prostate, colorectal, ovary, pancreatic, thyroid and esophageal Breast

41 patients 20 patients

IHC IHC/WB

↑ ↑

[2] [18]

8 patients/2 cell lines

IF/WB/WB

↓

[26]

Leukemia

94 patients

qRT-PCR

Heterogeneous

[16]

↑

[28]

Leukemia HDAC7

Breast Leukemia Endometrial

HDAC8

Breast

Leukemia

Endometrial

HDAC9

39 patients/24 cell lines HDAC10

Breast

8 patients/2 cell lines

IF/WB

↑

[26]

Leukemia

94 patients

qRT-PCR

Heterogeneous

[16]

↑

[28]

39 patients/24 cell lines HDAC11

Breast

8 patients/2 cell lines

IF/WB

↓

[26]

Leukemia

94 patients

qRT-PCR

Heterogeneous

[16]

93 patients

qRT-PCR/WB

↑

[7]

57 patients

IHC

↑

[11]

Pancreatic

TSA: trichostatin A; VPA: valproic acid; SFN: sulforaphane; SAHA: suberoylanilide hydroxamic acid.

Gene

Pancreatic

HDAC1 / HDAC2 HDAC1 / HDAC2 HDAC1 / HDAC3 HDAC3 HDAC3 HDAC1

TSA

Phi Van et al.[13]

FoxO3

Nasopharyngeal Ovarian Gastric Gastric Hepatic, lymphoma, myelomonocytic tumor Breast

Inhibitor TSA / VPA / Butyrate Depsipeptide / TSA Valproate VPA SFN TSA TSA TSA TSA SAHA TSA TSA VPA TSA / Apicidin / SAHA TSA TSA

HDAC3

-

You et al. [17]

Survivin

Oral

-

TSA

Liu et al. [9]

TOP1

Colorectal

-

TSA

Meisenberg et al. [11]

p21

APC DAB2 GATA4 GATA6 MUC2 RI p53 E-cadherin DTWD1 PUMA 5-HTT

Cancer Cell lines Colon Lung, gastric, colon Lung Endometrial Colon Colon Ovarian Ovarian Ovarian Pancreatic Breast Lung

Target protein HDAC1 / HDAC2 HDAC1 / HDAC2 HDAC2 HDAC2 HDAC1 / HDAC2 HDAC1 / HDAC2 HDAC1 / HDAC2 HDAC1

Reference Huang et al.[6] Lin et al.[8] Zhao[18] Hrzenjak et al.[5] Zhu et al. [19] Myzak et al.[12] Caslini et al.[2] Caslini et al.[2] Caslini et al.[2] Yamada et al[16] Ammanamanchi e Brattain[1] Kim et al.[7] Von Burstin et al.[15] Tong et al.[14] Hayashi et al.[4] Ma et al.[10] Feng et al.[3]

TSA: trichostatin A; VPA: valproic acid; SFN: sulforaphane; SAHA: suberoylanilide hydroxamic acid.

Table 2. Examples of genes probably silenced by HDACs and inhibitors utilized for gene reexpression.

Table 3. Summary of the involvement of most studied HATs and their target genes in cancer. HAT Family

HAT

Gene E2F1, cyclin D1 and cyclin E1

GNAT

GCN5

P300

-

NKG2D

-

Cyclin E Rb

Rb P53 AR

Prostate cancer

c-Myc

T-cell leukemia/ Lymphoma

MYC

ZNF384

MYST HBO1 MOZ

Melanoma Lung and hematopoietic cancer Gastric cancer Lymphoblastic leukemia -

p53, caspase-3

Tip60

Lung cancer

KLF4

p53

P300/CBP

Favoring oncogenesis

NF-κB AR NF-κB VHL Nrf2 AML-1

Prostate cancer Liver cancer -

Favoring Tumor suppression

Reference

-

Chen et al. [3]

Esophageal Squamous Cell Carcinoma Breast/Colon/ Osteosarcoma/Melanoma Glioma, ovarian, breast, colorectal, lung and pancreatic cancer Colon and cervical cancer

Bandyopadhyay et al.[2] Iyer et al.[11]

-

Ogiwara et al.[15]

Hu et al. [9] Hu et al. [10] Gayther et al.[6]

-

Shi et al. [19]

-

Qian et al. [17]

Lung cancer Skin tumor

Leduc et al.[14] Hobbs et al.[8] Gaughan et al., 200296; Halkidou et al.[5, 7]

-

Awasthi [1]

Metastasis Leukemia Renal cancer Leukemia

Kim et al.[13] Sharma et al. [18] Contzler et al.[4] Zhou et al.[20] Ohta et al.[16] Katsumoto et al.[12]

Table 4. HDAC inhibitors approved by FDA and same researches involving these drugs.

HDACi

Vorinostat (SAHA, Zolina)

Romidepsin (Istodax, FK228, FR901228,

Class

Approvation year

Association

Tumor target

Reference

2006

-

Cutaneous T-cell Lymphoma

Mann et al. [20]

-

Hematologic malignancies

Kelly et al. [12]

Temozolomide and radiotherapy

Glioblastoma

Shi et al. [30]

-

Endometrial

Bokhman[3]; Lax[15]; Sarfstein et al.[28]

Hypoxia and radiotherapy

Lung

Ma et al.[17]

-

Gastrointestinal cancer

Saelen et al.[27]

AA98

Ovarian cancer

Ma et al.[18]

Cisplatin

Adenoid Cystic Carcinoma

Almeida et al. [1]

Cisplatin

Rhabdomyosarcoma

Jarzab et al.[9]

Bevacizumab

Clear-cell Renal Cell Carcinoma

Pili et al.[23]

Bortezomib

Multiple myeloma

Nanavati et al. [21]

2009

-

Cutaneous T-cell Lymphoma

Piekarz et al.[22]; Whittaker et al.[36]

2011

-

Peripheral T-cell Lymphoma

Coiffier et al.[5] Shustov et al. [31]

Bortezomib

Lung

Karthik et al.[11]

-

Metastatic Breast cancer

Robertson et al. [26]

Gemcitabine

Pancreatic, Breast, Lung, and ovarian

Jones et al. [10]

-

Thyroid

Amiri-Kordestani et al. [2]

-

Hepatocellular carcinoma

Sun et al. [32]

-

Peripheral T-cell Lymphoma

Poole [24]

-

Malignant pleural mesothelioma

Ramalingam et al. [25]

-

Ovarian tumors

Mackay et al. [19]

-

Thymic epithelial cancer

Giaccone et al. [8]

-

Mielodysplastyc syndrome

Cashen et al. [4]

Carboplatin and paclitaxel

Ovarian

Dizon, Blessing, et al.[6]; Dizon, Damstrup, et al.[7]

-

Acute myeloid leukemia

Kirschbaum et al. [13]

Cisplatin, doxorubicin, cyclophosphamide

Thymic epithelial tumors

Thomas et al. [33]

-

Liver

Ma et al. [16]

-

Acute promyelocytic leukemia

Savickiene et al. [29]

Hidroxamic acid In research

Cyclic peptide

depsipeptide) In research

2014

Belinostat (Beleodaq, PXD-101)

Hidroxamic acid In research

Doxorubicin

Soft Tissue Sarcomas

Vitfell-Rasmussen et al. [35]

Cisplatin

Squamous Cell Carcinoma

Kong et al. [14]

Cisplatin

Lung Cancer

To et al. [34]