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Year : 2013  |  Volume : 9  |  Issue : 5  |  Page : 86-91

The landscape of histone acetylation involved in epithelial-mesenchymal transition in lung cancer

1 Department of Thoracic Surgery, Shandong Provincial Hospital, Affiliated to Shandong University, Jinan, China
2 Shandong Health Education and Training Center, Jinan, 250014, China

Date of Web Publication30-Sep-2013

Correspondence Address:
Zuogong Liu
Shandong Health Education and Training Center, Jinan, 250014
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-1482.119113

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 > Abstract 

Epithelial-mesenchymal transition (EMT) has been widely accepted as the early stage of tumor metastasis, which is accomplished by a group of transcription factors based on cancer genome. However, with the progress of epigenome profiling technique, it has been demonstrated that aberrant histone modifications especially acetylation play an important role in EMT and cancer metastasis. Besides this, numerous studies have elucidated the mechanisms of histone acetyltransferases and deacetylases involved in EMT. Moreover, the network of these histone-related proteins and those transcription factors that play key roles in EMT is under increasing investigation. In addition, the crosstalk among deoxyribonucleic acid methylation, histone acetylation and micro Ribonucleic acid, three major epigenetic modifications, is also an important part in tumor progression. Here, we explore the mechanisms of histone acetylation in EMT and discuss the potential clinical strategies using the epigenetic drugs.

Keywords: Histone acetylation, epithelial-mesenchymal transition, histone deacetylase, histone lysine acetyltransferases

How to cite this article:
Zhang L, Liu Z, Ma W, Wang B. The landscape of histone acetylation involved in epithelial-mesenchymal transition in lung cancer. J Can Res Ther 2013;9, Suppl S1:86-91

How to cite this URL:
Zhang L, Liu Z, Ma W, Wang B. The landscape of histone acetylation involved in epithelial-mesenchymal transition in lung cancer. J Can Res Ther [serial online] 2013 [cited 2021 Feb 25];9:86-91. Available from: https://www.cancerjournal.net/text.asp?2013/9/5/86/119113

 > Introduction Top

Lung cancer, divided into two types, which are small-cell lung carcinoma and non-small-cell lung carcinoma (NSCLC), has been the leading cause of death world-wide. Although the underlying mechanisms have been studied for many years, its therapeutic treatments are still disappointing with 5 years survival rates of <10%. [1] Currently, the major therapeutic obstacles are tumor recurrence and metastasis even after surgical resection, which are the main cause of mortality. Epithelial to mesenchymal transition (EMT) are the early stage of metastasis, which endows the cancer cells with the metastatic ability and self-renewal potential [2] and it has been evidenced circumstantially that EMT occurs in vivo in lung carcinogenesis. [3] Chemotherapy and radiotherapy are the most common treatments in the recurrent lung cancer; however, the consequence of this combination treatment is still disappointing. [4] Thus, it is urgent to elucidate thoroughly the underlying molecular mechanisms, which will help to provide enough potential targets for clinical applications. For this purpose, several groups have paid more attention on defining the roles of the epigenetic modification, especially histone modifications, in tumor progression including lung cancer. [5],[6],[7],[8]

Since the importance of epigenetic modifications, especially the histone modifications, in EMT, the preinvasive state of cancer metastasis, in this review we will summarize the current knowledge of histone modifications during the process of EMT especially in lung cancer. Secondly, we will show a complex, but delicate network in which each epigenetic modification is orchestrated synergistically. Finally, we will introduce several Food and Drug Administration (FDA)-proved drugs, which specifically target histone acetylases and deacetylases and other potential therapeutic strategies combined with methyltransferase inhibitors.

 > EMT in Lung Cancer Top

During the process of EMT, cells undergo the morphological changing from epithelial to fibroblastic cells, loosening the cell-cell adheren junctions, increasing the expression of matrix-enzymatic proteins thus leading to the higher motility, heightening the anti-apoptotic ability. [9] EMT is trigged by a number of stimuli including growth factors, such as transforming growth factor β (TGF-β), extracellular interactions and hypoxia. [10],[11] A group of transcription factors are induced to response to these stimulation, including homeobox protein Goosecoid, [12] the zinc-finger protein Snail1 and Snai2 (Slug), [13],[14] the basic helix-loop-helix (bHLH) protein Twist 1, [15],[16] the forkhead box proteins (FOXC1) [17],[18] and FOXC2, [19] and the zinc-finger, E-box-binding proteins Zeb1 [20] and Sip1 (Zeb2). [21] Several of these transcription factors regulate the same downstream target, E-cadherin, whose loss is the marker of the initiation of EMT. [22],[23],[24] Interestingly, EMT results in endowing cancer cells with stem cells-like characteristics, [25],[26] which help cancerous cells invade local tissues and resist from immune-attack. [27] In addition, micro Ribonucleic acid (microRNA) such as miR200 family members are reported to be down-regulated during EMT process, [28],[29] which in turn led to up-regulate the expressions of several key target genes, such as Zeb1 and Zeb2, the mesenchymal marker genes. [30] Recently, researchers pay more attentions on the roles of epigenetic regulation in EMT process for the hypothesis that not only genetic, but also epigenetic alterations have important influences on tumorigenesis. [31]

Researchers have provided evidences that EMT occurs in vivo in lung cancers. By examine the expression of various epithelial and mesenchymal markers in a number of lung adenocarcinoma and squamous-cell carcinomas as well as normal epithelia and premalignant lesions, Prudkin and his colleagues found that mesenchymal markers expressed lower in dysplastic lesions compared with squamous-cell carcinomas. [32] And E-cadherin expressed higher in the metastatic lesions in the brain from these tumors. [33] All these results indicated that EMT occurred during lung carcinogenesis as well as a reversible process MET in the metastatic sites.

Histone modifications including methylation, acetylation and ubiquitination, are alternative mechanisms, which are essential to gene activation or silencing. Many studies showed that histone acetylation/deacetylation has an important influence on the regulation of tumorigenesis, including EMT. [34],[35] Indeed, histone acetylation is often associated with a more "open" chromatin conformation [36] and chromatin assembly [37] and deacetylation just the opposite. [38] Acetylation/deacetylation is mainly regulated by the competing activities of two enzymatic families, the histone lysine acetyltransferases (HATs) and the histone deacetylases (HDACs). [39]

 > Histone Acetyl-Transferases and HDACS Top

HATs and HDACs are a couple of histone acetylation regulators, functioning conversely and maintaining the global balance of lysine acetylation status in vivo.

HATs include three major families, [GCN5 (general control of amino acid synthesis 5)-related N-acetyltransferase] (GANT) superfamily, [MOZ (monocytic leukemic zinc-finger protein), Ybf2/Sas3, Sas2 and TIP60] (MYST) family and CBP/p300 [CREB (cAMP-response-element-binding protein)-binding protein]/E1A-associated protein of 300 kDa family. [40],[41],[42] And several HATs is involved in neoplastic transformation [43] and is closely correlated with a number of viral oncoproteins. [44] Furthermore, recurrent chromosomal translocation or coding mutations is demonstrated to be associated with various HATs in a broad range of solid and hematological malignancies. [45],[46] The ultimately generating oncoproteins possess both the deoxyribonucleic acid (DNA) binding domain and the other coactivator domain, which contribute to cancer.

HDACs belong to an ancient and highly conserved superfamily from prokaryotes to humans. According to HDACs' structure, enzymatic function, subcellular localization and expression patterns, HDACs are divided into four classes (class I, IIa, IIb and IV). [47] Besides these classical HDACs, it has been found another group of HDAC, called the Sirtuins, which are sometimes referred as class III HDACs. [38] Abundant data indicated that aberrant activity of HDACs is directly correlated with the progression of various tumors mainly through its transcriptional repression activity. [48]

Interestingly, some non-histone proteins, especially some important oncogenes or tumor suppressors, such as MYC and p53, are the substrates of acetylation/deacetylation. [49] All major acetylation sites of p53 has been identified, [50] and further investigation demonstrated that the acetylation of p53 is essential to its activation for it destabilizes the p53-Mdm2 interaction and facilitate p53-dependent growth arrest and apoptosis. [51] Recently, it has been shown that through repressing MYC transcriptional activity, silent information regulator (Sirt6) inhibited the number, size and aggressiveness of tumors. [52]

 > The Regulation of Histone Acetylation on E-Cadherin in EMT Top

One major hallmark of EMT is the deregulation of E-cadherin, a calcium-dependent transmembrane glycoprotein. [9] Aberrant expression of E-cadherin results in dysfunction of the cell-cell junctions, triggering cancer cells invasion and metastasis. [53],[54] In fact, loss of E-cadherin expression or function by genetic or epigenetic aberrations is a common phenomenon in lung cancer and is associated with poor patient prognosis. [3] Increasing evidences support the idea that histone acetylation/deacetylation presented as a regulator of E-cadherin during EMT in several cancers, including lung cancer. [6]

The activation of E-cadherin could repression the EMT occurrence, which is dependent on HDAC activity, evidenced by a transcriptional repressor complex containing Snail and HDAC1 and HDAC2 in highly metastatic pancreatic cancer cells. [55]

In fact, several HDAC-containing complexes appear to play distinct roles in regulation of E-cadherin during EMT. A specific HDAC inhibitor, trichostatin A (TSA). A could assemble a complex with activated Estrogen receptor-α (ER-α) and nuclear receptor co-repressor [56] and the complex directly binds to the promoter of slug who is a marker of mesenchymal status and represses the slug transcription. [57] Subsequently, the expression of E-cadherin is increased. [58]

Similarly, another HDAC-containing complexes, the Mi2/nucleosome remodeling and deacetylase (Mi2/NuRD) complex, is identified to interact with TWIST, a major regulator in EMT. [59] The interaction, which activates through the components named metastasis-associated protein 2 (MTA2), RbAp46, Mi2 and HDAC2, recruits the components to the proximal regions of the E-cadherin promoter for transcriptional repression. [60] Subsequently, the loss expression of E-cadherin led to cell migration and invasion in culture and lung metastasis in mice. [61]

The HDACs are also involved in regulation of E-cadherin by non-coding microRNAs during EMT. MiR200b and miR200c increase the expression of E-cadherin in human breast cancer cells. Indeed, miR200b and miR200c have an effect on histone 3 (H3) acetylation at E-cadherin promoter. However, the H3 acetylation not only disrupted the complex formation of ZEB1 and HDAC, but also inhibited SIRT1 expression. [62]

 > The Influence of Histone Acetylation on TGF-B Signaling Pathway in EMT Top

Increasing evidences support that TGF-β may play a key role in lung carcinogenesis, especially in EMT process. [3] The direct downstream target of activated TGF-β is the Smad family. The activated TGF-β binding to its specific receptor would phosphorylate Samd 2 and Smad 3 proteins, which further recruited Smad 4 protein. The Samd complex translocated into the nucleus and regulated the transcription by directly binding to the promoter of its downstream target, along with recruiting the specific transcriptional co-activators or co-repressors, such as p300/CBP and HDACs.

Besides Smad complexes, other alternative mechanisms have been elucidated in TGFβ-activated EMT. It is reported that the expression of MTA1, which is demonstrated to be a component of NuRD complex, is stimulated by TGFβ in mammary epithelial cells. Furthermore, MTA1/polymerase II/activator protein-1 (AP-1) complex stimulates FosB transcription by binding to its chromatin. In turn, FosB formed the complex with histone acetylase 2 to repress the expression of E-cadherin. [63]

In other cases, TGFβRII receptor, the key component of TGFβ signaling pathway, is reported to be downregulated by connective tissue growth factor (CCN5). CCN5, a member of the CCN family, functions as a transcriptional repressor through association with HDAC1 and it has been demonstrated that the expression of TGFβRII receptor is repressed through the recruitment of CCN5 to the promoter of TGFβRII receptor. Consistently, CCN5 also represses the transcriptional activation and tumor invasion induced by TGFβ, suggesting that CCN5 play a key role in inhibiting tumor progression by repressing genes expression, which are involved in the TGFβ signaling cascade. [64]

 > The Correlation of Histone Acetylation and Hypoxia in EMT Top

Hypoxia is one of the major mechanisms, which is responsible for tumor angiogenesis, metastasis and poor prognosis. [65] The hypoxia signal is mainly transduced by a hypoxia-inducible factor, which includes three members (HIF-1, 2 and 3). HIF is a heterodimer complex consisting of two bHLH transcriptional factors, which are oxygen-regulated α proteins and constitutively-expressed β protein. [66] In fact, HIF-1 α overexpression induced the expression of EMT regulators, such as Twist in NSCLC cells H1299. [67] Moreover, overexpression of HIF1-1 α, TWIST or SNAIL is correlated with poor prognosis in NSCLC patients. [3] In addition, HIF-2 α cooperates with RAS to promote lung tumorigenesis exhibiting EMT features in mouse model of lung cancer. [68] Recently, Yang's reports illustrated a delicate picture, in which hypoxia-induced HDAC downregulated long non-coding RNA-Low Expression in Tumor (LncRNA-LET) in hepatocellular carcinoma, colorectal cancer and squamous-cell lung carcinomas by reducing the histone acetylation-mediated modulation of the IncRNA-LET promoter region. Moreover, they demonstrated that the down-regulated LncRNA-LET further stabilized nuclear factor 90 protein, which leads to hypoxia-induced cancer cell invasion. [88]

 > The Crosstalk of DNA Methylation, Histone Acetylation and microRNA Top

Recent advances in genomic technologies have placed us in a position to initiate large-scale studies of human disease-associated epigenetic variation, which have gained enough attention in tumorigenesis for the reason that mutations in epigenetic regulators continued to emerge from subsequent cancer studies and have surged in recent large-scale sequencing efforts. [69] It has been analyzed that epigenetic regulators are mutated in about half of hepatocellular carcinomas [70] and bladder cancer [71] and represent 6 of the 12 most significantly mutated genes in medulloblastoma. [72]

DNA methylation, histone acetylation and microRNA is referred to three major epigenetic modifications. [73] Indeed, alterations in DNA methylation, histone acetylation, polycomb, miRNAs and chromatin remodeling complex function are mechanisms that directly contribute to tumorigenesis. These modifications do not function alone, instead, they form a huge network in which they counteract mutually and work synergistically. [31],[74]

EZH2, a histone lysine-specific methyltransferase, is physically and functionally linked to HDAC1 and HDAC2, which are frequently found overexpressed in various types of cancer. [75] Furthermore, HATs such as G9a and aberrant fusion proteins formed through chromosomal translocations of HAT and HAT-related genes (MOZ, MORF, CBP and p300) [40] or chromosomal translocations of MLL, have been related to cancer. [76]

LSD1, another histone lysine-specific demethylase, is a subunit of NuRD complex and a suppressor of metastasis. [77] LSD1 containing NuRD complex binds the promoters of TGFβ and suppresses its expression. Consistent with the critical roles of TGFβ in the invasion and metastasis, overexpression of LSD1 reduced breast cancer metastasis to the lung, whereas its knockdown enhanced metastasis. Although the demethylase activity of LSD1 was not investigated in the study, it is perceivable that H3K4 demethylation by LSD1 and histone deacetylation by the NuRD complex coordinately blocked the binding of transcription factors to suppress TGFβ.

Aberrant expression of some of miRNAs is related to tumor growth and metastasis. [78],[79],[80] Recently, it was found that the expression of miRNAs may also be regulated by promoter DNA methylation, adding a new level of complexity to the epigenetic regulation of tumorigenesis. [81],[82]

The class III HDAC, SIRT1, a proposed oncogene in breast cancer, is overexpressed upon EMT-like transformation and that epigenetic silencing of miR-200a contributes at least in part to the overexpression of SIRT1. [83]

All the data show that the epigenetic modification might be not isolated. They influence and/or regulate each other, evenly they cooperate with each other to participate in lung cancer progression. [84]

 > The Clinical Application Top

Epigenetic changes are responsible for at least 50% of gene inactivating events in cancer and they are potentially reversible, whereas genetic changes are not. HDAC inhibitors, by blocking removal of acetyl groups from lysine residues of histone tails, alter the packaging of genes in chromatin such that those are pathogenically silenced are switched back on. [85] One major issue with HDAC inhibitor is that they target not only the lysines in histones, but also those in other proteins, leading to unwanted side effects. [86] More works needed to be carried out to know much more about the mechanisms of action of the different classes of HDACs.

Epigenetic drug combination therapy is on the way to treat diseases. Kapil Bhalla and his team have treated an acute myeloid leukemia cell line with a combination of the histone methyltransferase inhibitor deazaneplanocin A (DZNep) and the HDAC inhibitor panobinostat. [87] Each drug alone reactivated pathogenically methylated genes such as the tumor suppressor p16, inducing apoptosis of 20-30% of the cancer cells. However, treatment with both DZNep and panobinostat induced apoptosis of 75% of the leukemia cells. In a clinical trial, Bhalla's team added the HDAC inhibitor entinostat twice during a 5-azacytidine treatment regimen and observed slowed cancer growth in 46% patients.

 > Conclusions and Perspectives Top

Combining the huge amounts of information digged from genome-wide and epigenome-wide profiling, people is paying great effort to draw a blueprint describing a more accurate and detailed molecular mechanisms, in which histone acetylation is involved underlying EMT process in lung carcinogenesis. It has been widely accepted that histone acetylation play an important role in the regulation of carcinogenesis, especially in EMT, the early stage of cancer metastasis. Aberrations of any of three major histone proteins, HATs, HDACs and histone readers have been demonstrated to be closely correlated with tumor progression, including lung cancer. Through directly regulating the acetylation status of EMT markers, such as EMT, TWIST, Slug, HATs and HDACs have effects on EMT. Besides this, TGFβ is also involved in the histone acetylation. Moreover, microenvironment, such as hypoxia, is demonstrated to be correlated with histone acetylation to affect EMT process. Most importantly, accumulating evidences support the idea that the vivid crosstalk exists among DNA methylation, histone acetylation and microRNA. In addition, increased understanding of the mechanisms of histone acetylation and its interaction with other epigenetic modifications in EMT will prove the way to develop more potential therapeutic strategies with higher efficiency and lower side-effects.

 > References Top

1.Yang P. Epidemiology of lung cancer prognosis: Quantity and quality of life. Methods Mol Biol 2009;471:469-86.  Back to cited text no. 1
2.Ito M, Okita R, Tsutani Y, Mimura T, Kawasaki Y, Miyata Y, et al. Lung metastasis of adenoid cystic carcinoma, which mimicked primary lung cancer. Thorac Cancer 2013;4:327-9.  Back to cited text no. 2
3.Sato M, Shames DS, Hasegawa Y. Emerging evidence of epithelial-to-mesenchymal transition in lung carcinogenesis. Respirology 2012;17:1048-59.  Back to cited text no. 3
4.Liu J, Zhong X, Li J, Liu B, Guo S, Chen J, et al. Screening and identification of lung cancer metastasis-related genes by suppression subtractive hybridization. Thorac Cancer 2012;3:207-16.  Back to cited text no. 4
5.Juergens RA, Rudin CM. Aberrant epigenetic regulation. Am Soc Clin Oncol Educ Book 2013;2013:295-300.  Back to cited text no. 5
6.Wang Y, Shang Y. Epigenetic control of epithelial-to-mesenchymal transition and cancer metastasis. Exp Cell Res 2013;319:160-9.  Back to cited text no. 6
7.Hu M, Yao J, Cai L, Bachman KE, van den Brûle F, Velculescu V, et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet 2005;37:899-905.  Back to cited text no. 7
8.Kumar R, Xi Y. MicroRNA, epigenetic machinery and lung cancer. Thorac Cancer 2011;2:35-44.  Back to cited text no. 8
9.Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: Acquisition of malignant and stem cell traits. Nat Rev Cancer 2009;9:265-73.  Back to cited text no. 9
10.Lawless MW, O'Byrne KJ, Gray SG. Targeting oxidative stress in cancer. Expert Opin Ther Targets 2010;14:1225-45.  Back to cited text no. 10
11.Gao D, Vahdat LT, Wong S, Chang JC, Mittal V. Microenvironmental regulation of epithelial-mesenchymal transitions in cancer. Cancer Res 2012;72:4883-9.  Back to cited text no. 11
12.Taube JH, Herschkowitz JI, Komurov K, Zhou AY, Gupta S, Yang J, et al. Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proc Natl Acad Sci U S A 2010;107:15449-54.  Back to cited text no. 12
13.Scanlon CS, Van Tubergen EA, Inglehart RC, D'Silva NJ. Biomarkers of epithelial-mesenchymal transition in squamous cell carcinoma. J Dent Res 2013;92:114-21.  Back to cited text no. 13
14.Shih JY, Yang PC. The EMT regulator slug and lung carcinogenesis. Carcinogenesis 2011;32:1299-304.  Back to cited text no. 14
15.Kang Y, Massagué J. Epithelial-mesenchymal transitions: Twist in development and metastasis. Cell 2004;118:277-9.  Back to cited text no. 15
16.Qin Q, Xu Y, He T, Qin C, Xu J. Normal and disease-related biological functions of Twist1 and underlying molecular mechanisms. Cell Res 2012;22:90-106.  Back to cited text no. 16
17.Bloushtain-Qimron N, Yao J, Snyder EL, Shipitsin M, Campbell LL, Mani SA, et al. Cell type-specific DNA methylation patterns in the human breast. Proc Natl Acad Sci U S A 2008;105:14076-81.  Back to cited text no. 17
18.Yu M, Bardia A, Wittner BS, Stott SL, Smas ME, Ting DT, et al. Circulating breast tumor cells exhibit dynamic changes in epithelial and mesenchymal composition. Science 2013;339:580-4.  Back to cited text no. 18
19.Mani SA, Yang J, Brooks M, Schwaninger G, Zhou A, Miura N, et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc Natl Acad Sci U S A 2007;104:10069-74.  Back to cited text no. 19
20.Browne G, Sayan AE, Tulchinsky E. ZEB proteins link cell motility with cell cycle control and cell survival in cancer. Cell Cycle 2010;9:886-91.  Back to cited text no. 20
21.Bindels S, Mestdagt M, Vandewalle C, Jacobs N, Volders L, Noël A, et al. Regulation of vimentin by SIP1 in human epithelial breast tumor cells. Oncogene 2006;25:4975-85.  Back to cited text no. 21
22.Yang MH, Hsu DS, Wang HW, Wang HJ, Lan HY, Yang WH, et al. Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nat Cell Biol 2010;12:982-92.  Back to cited text no. 22
23.Leong KG, Niessen K, Kulic I, Raouf A, Eaves C, Pollet I, et al. Jagged1-mediated Notch activation induces epithelial-to-mesenchymal transition through slug-induced repression of E-cadherin. J Exp Med 2007;204:2935-48.  Back to cited text no. 23
24.Byles V, Zhu L, Lovaas JD, Chmilewski LK, Wang J, Faller DV, et al. SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene 2012;31:4619-29.  Back to cited text no. 24
25.Nahas GR, Patel SA, Bliss SA, Rameshwar P. Can breast cancer stem cells evade the immune system? Curr Med Chem 2012;19:6036-49.  Back to cited text no. 25
26.Esteban MA, Bao X, Zhuang Q, Zhou T, Qin B, Pei D. The mesenchymal-to-epithelial transition in somatic cell reprogramming. Curr Opin Genet Dev 2012;22:423-8.  Back to cited text no. 26
27.Bansa A. Cancer stem cells in the origin and transformation of barrett's esophagus: Current knowledge and areas of uncertainty. Immunogastroenterology 2013;2:9.  Back to cited text no. 27
28.Mongroo PS, Rustgi AK. The role of the miR-200 family in epithelial-mesenchymal transition. Cancer Biol Ther 2010;10:219-22.  Back to cited text no. 28
29.Manavalan TT, Teng Y, Litchfield LM, Muluhngwi P, Al-Rayyan N, Klinge CM. Reduced expression of miR-200 family members contributes to antiestrogen resistance in LY2 human breast cancer cells. PLoS One 2013;8:e62334.  Back to cited text no. 29
30.Hill L, Browne G, Tulchinsky E. ZEB/miR-200 feedback loop: At the crossroads of signal transduction in cancer. Int J Cancer 2013;132:745-54.  Back to cited text no. 30
31.Sandoval J, Esteller M. Cancer epigenomics: Beyond genomics. Curr Opin Genet Dev 2012;22:50-5.  Back to cited text no. 31
32.Prudkin L, Liu DD, Ozburn NC, Sun M, Behrens C, Tang X, et al. Epithelial-to-mesenchymal transition in the development and progression of adenocarcinoma and squamous cell carcinoma of the lung. Mod Pathol 2009;22:668-78.  Back to cited text no. 32
33.Pezzilli R. Serum E-cadherin and hepatocyte growth factor in acute pancreatitis: Exploring time course, and severity assessment. Immunogastroenterology 2013;2:57.  Back to cited text no. 33
34.Micalizzi DS, Farabaugh SM, Ford HL. Epithelial-mesenchymal transition in cancer: Parallels between normal development and tumor progression. J Mammary Gland Biol Neoplasia 2010;15:117-34.  Back to cited text no. 34
35.Giudice FS, Pinto DS Jr, Nör JE, Squarize CH, Castilho RM. Inhibition of histone deacetylase impacts cancer stem cells and induces epithelial-mesenchyme transition of head and neck cancer. PLoS One 2013;8:e58672.  Back to cited text no. 35
36.Gray SG, Teh BT. Histone acetylation/deacetylation and cancer: An "open" and "shut" case? Curr Mol Med 2001;1:401-29.  Back to cited text no. 36
37.Roth SY, Allis CD. Histone acetylation and chromatin assembly: A single escort, multiple dances? Cell 1996;87:5-8.  Back to cited text no. 37
38.Glozak MA, Seto E. Histone deacetylases and cancer. Oncogene 2007;26:5420-32.  Back to cited text no. 38
39.Shahbazian MD, Grunstein M. Functions of site-specific histone acetylation and deacetylation. Annu Rev Biochem 2007;76:75-100.  Back to cited text no. 39
40.Yang XJ. The diverse superfamily of lysine acetyltransferases and their roles in leukemia and other diseases. Nucleic Acids Res 2004;32:959-76.  Back to cited text no. 40
41.Allis CD, Berger SL, Cote J, Dent S, Jenuwien T, Kouzarides T, et al. New nomenclature for chromatin-modifying enzymes. Cell 2007;131:633-6.  Back to cited text no. 41
42.Roth SY, Denu JM, Allis CD. Histone acetyltransferases. Annu Rev Biochem 2001;70:81-120.  Back to cited text no. 42
43.Jiang Y, Hatzi K, Shaknovich R. Mechanisms of epigenetic deregulation in lymphoid neoplasms. Blood 2013;121:4271-9.  Back to cited text no. 43
44.Di Cerbo V, Schneider R. Cancers with wrong HATs: The impact of acetylation. Brief Funct Genomics 2013;12:231-43.  Back to cited text no. 44
45.Perez-Campo FM, Costa G, Lie-a-Ling M, Kouskoff V, Lacaud G. The MYSTerious MOZ, a histone acetyltransferase with a key role in haematopoiesis. Immunology 2013;139:161-5.  Back to cited text no. 45
46.Panagopoulos I, Micci F, Thorsen J, Gorunova L, Eibak AM, Bjerkehagen B, et al. Novel fusion of MYST/Esa1-associated factor 6 and PHF1 in endometrial stromal sarcoma. PLoS One 2012;7:e39354.  Back to cited text no. 46
47.de Ruijter AJ, van Gennip AH, Caron HN, Kemp S, van Kuilenburg AB. Histone deacetylases (HDACs): Characterization of the classical HDAC family. Biochem J 2003;370:737-49.  Back to cited text no. 47
48.Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: Implications for disease and therapy. Nat Rev Genet 2009;10:32-42.  Back to cited text no. 48
49.Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone proteins. Gene 2005;363:15-23.  Back to cited text no. 49
50.Gu W, Roeder RG. Activation of p53 sequence-specific DNA binding by acetylation of the p53 C-terminal domain. Cell 1997;90:595-606.  Back to cited text no. 50
51.Tang Y, Zhao W, Chen Y, Zhao Y, Gu W. Acetylation is indispensable for p53 activation. Cell 2008;133:612-26.  Back to cited text no. 51
52.Sebastián C, Zwaans BM, Silberman DM, Gymrek M, Goren A, Zhong L, et al. The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism. Cell 2012;151:1185-99.  Back to cited text no. 52
53.Wells A, Yates C, Shepard CR. E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis 2008;25:621-8.  Back to cited text no. 53
54.Schmalhofer O, Brabletz S, Brabletz T. E-cadherin, beta-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev 2009;28:151-66.  Back to cited text no. 54
55.von Burstin J, Eser S, Paul MC, Seidler B, Brandl M, Messer M, et al. E-cadherin regulates metastasis of pancreatic cancer in vivo and is suppressed by a SNAIL/HDAC1/HDAC2 repressor complex. Gastroenterology 2009;137:361-71, 3711.  Back to cited text no. 55
56.Heltweg B, Jung M. A microplate reader-based nonisotopic histone deacetylase activity assay. Anal Biochem 2002;302:175-83.  Back to cited text no. 56
57.Wu Y, Kawate H, Ohnaka K, Nawata H, Takayanagi R. Nuclear compartmentalization of N-CoR and its interactions with steroid receptors. Mol Cell Biol 2006;26:6633-55.  Back to cited text no. 57
58.Ye Y, Xiao Y, Wang W, Yearsley K, Gao JX, Shetuni B, et al. ERalpha signaling through slug regulates E-cadherin and EMT. Oncogene 2010;29:1451-62.  Back to cited text no. 58
59.Sims JK, Wade PA. Mi-2/NuRD complex function is required for normal S phase progression and assembly of pericentric heterochromatin. Mol Biol Cell 2011;22:3094-102.  Back to cited text no. 59
60.Chao YL, Shepard CR, Wells A. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer 2010;9:179.  Back to cited text no. 60
61.Fu J, Qin L, He T, Qin J, Hong J, Wong J, et al. The TWIST/Mi2/NuRD protein complex and its essential role in cancer metastasis. Cell Res 2011;21:275-89.  Back to cited text no. 61
62.Tryndyak VP, Beland FA, Pogribny IP. E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int J Cancer 2010;126:2575-83.  Back to cited text no. 62
63.Pakala SB, Singh K, Reddy SD, Ohshiro K, Li DQ, Mishra L, et al. TGF-β1 signaling targets metastasis-associated protein 1, a new effector in epithelial cells. Oncogene 2011;30:2230-41.  Back to cited text no. 63
64.Sabbah M, Prunier C, Ferrand N, Megalophonos V, Lambein K, De Wever O, et al. CCN5, a novel transcriptional repressor of the transforming growth factor β signaling pathway. Mol Cell Biol 2011;31:1459-69.  Back to cited text no. 64
65.Maxwell PH. The HIF pathway in cancer. Semin Cell Dev Biol 2005;16:523-30.  Back to cited text no. 65
66.Rankin EB, Giaccia AJ. The role of hypoxia-inducible factors in tumorigenesis. Cell Death Differ 2008;15:678-85.  Back to cited text no. 66
67.Yang MH, Wu KJ. TWIST activation by hypoxia inducible factor-1 (HIF-1): Implications in metastasis and development. Cell Cycle 2008;7:2090-6.  Back to cited text no. 67
68.Mazumdar J, Hickey MM, Pant DK, Durham AC, Sweet-Cordero A, Vachani A, et al. HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc Natl Acad Sci U S A 2010;107:14182-7.  Back to cited text no. 68
69.Wu MZ, Tsai YP, Yang MH, Huang CH, Chang SY, Chang CC, et al. Interplay between HDAC3 and WDR5 is essential for hypoxia-induced epithelial-mesenchymal transition. Mol Cell 2011;43:811-22.  Back to cited text no. 69
70.Fujimoto A, Totoki Y, Abe T, Boroevich KA, Hosoda F, Nguyen HH, et al. Whole-genome sequencing of liver cancers identifies etiological influences on mutation patterns and recurrent mutations in chromatin regulators. Nat Genet 2012;44:760-4.  Back to cited text no. 70
71.Gui Y, Guo G, Huang Y, Hu X, Tang A, Gao S, et al. Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder. Nat Genet 2011;43:875-8.  Back to cited text no. 71
72.Jones DT, Jäger N, Kool M, Zichner T, Hutter B, Sultan M, et al. Dissecting the genomic complexity underlying medulloblastoma. Nature 2012;488:100-5.  Back to cited text no. 72
73.Blair LP, Yan Q. Epigenetic mechanisms in commonly occurring cancers. DNA Cell Biol 2012;31 Suppl 1:S49-61.  Back to cited text no. 73
74.Cedar H, Bergman Y. Linking DNA methylation and histone modification: Patterns and paradigms. Nat Rev Genet 2009;10:295-304.  Back to cited text no. 74
75.Halkidou K, Gaughan L, Cook S, Leung HY, Neal DE, Robson CN. Upregulation and nuclear recruitment of HDAC1 in hormone refractory prostate cancer. Prostate 2004;59:177-89.  Back to cited text no. 75
76.Krivtsov AV, Armstrong SA. MLL translocations, histone modifications and leukaemia stem-cell development. Nat Rev Cancer 2007;7:823-33.  Back to cited text no. 76
77.Wang Y, Zhang H, Chen Y, Sun Y, Yang F, Yu W, et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 2009;138:660-72.  Back to cited text no. 77
78.Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 2010;12:247-56.  Back to cited text no. 78
79.Valastyan S, Reinhardt F, Benaich N, Calogrias D, Szász AM, Wang ZC, et al. A pleiotropically acting microRNA, miR-31, inhibits breast cancer metastasis. Cell 2009;137:1032-46.  Back to cited text no. 79
80.Makowiecki C, Nolte A, Sutaj B, Keller T, Avci-Adali M, Stoll H, et al. New basic approach to treat Non-small-cell-lung-cancer based on RNA-Interference. Thorac Cancer 2013; In press.  Back to cited text no. 80
81.Bandres E, Agirre X, Bitarte N, Ramirez N, Zarate R, Roman-Gomez J, et al. Epigenetic regulation of microRNA expression in colorectal cancer. Int J Cancer 2009;125:2737-43.  Back to cited text no. 81
82.Lujambio A, Ropero S, Ballestar E, Fraga MF, Cerrato C, Setién F, et al. Genetic unmasking of an epigenetically silenced microRNA in human cancer cells. Cancer Res 2007;67:1424-9.  Back to cited text no. 82
83.Eades G, Yao Y, Yang M, Zhang Y, Chumsri S, Zhou Q. miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells. J Biol Chem 2011;286:25992-6002.  Back to cited text no. 83
84.Song X, Lu F, Liu R-Y, Lei Z, Zhao J, Zhou Q, et al. Association between the ATF3 gene and non-small cell lung cancer. Thorac Cancer 2012;3:217-23.  Back to cited text no. 84
85.Guo YF, Wang XB, Tian XY, Li Y, Li B, Huang Q, et al. Tumor-derived hepatocyte growth factor is associated with poor prognosis of patients with glioma and influences the chemosensitivity of glioma cell line to cisplatin in vitro. World J Surg Oncol 2012;10:128.  Back to cited text no. 85
86.Robey RW, Chakraborty AR, Basseville A, Luchenko V, Bahr J, Zhan Z, et al. Histone deacetylase inhibitors: Emerging mechanisms of resistance. Mol Pharm 2011;8:2021-31.  Back to cited text no. 86
87.Fiskus W, Wang Y, Sreekumar A, Buckley KM, Shi H, Jillella A, et al. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells. Blood 2009;114:2733-43.  Back to cited text no. 87
88.Yang F, Huo XS, Yuan SX, Zhang L, Zhou WP, Wang F, et al. Repression of the Long Noncoding RNA-LET by Histone Deacetylase 3 Contributes to Hypoxia-Mediated Metastasis. Mol Cell 2013;49: 1083-96.  Back to cited text no. 88


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