Cancer remains one of the major health problems in the world (You and Jones, 2012; Velerken, Hurt, and Hollingsworth, 2012). For a long time, the basis of cancer development was taken to be genetic imbalances brought about by various factors some of which were environmental. However, from the mid-1940s, advanced technology has revealed factors outside the genetic make-up of an individual also contribute to the initiation and development of cancer.
This has been termed epigenetics. Correct gene expression is essential for normal cell development and growth (Velerken, Hurt, and Hollingsworth, 2012). One way this is achieved is through epigenetic modification of both DNA and histones (Velerken, Hurt, and Hollingsworth, 2012). Epigenetics, a term first used by Conrad Waddington in 1939 is now broadly accepted to mean “the study of heritable changes in gene expression that occur independently of changes in primary DNA sequence” (Sharma, Kelly, and Jones, 2010).
Epigenetics is a possible explanation for complex biological puzzles such as phenotypic differences in individuals with possible identical DNA sequences such as monozygotic twins and cloned organisms (Esteller, 2008). It has been postulated epigenetic may precede classical tumor mutation events such as mutation of tumor suppressor, proto-oncogene, and genomic instability (Rodriguez-Paredes and Esteller, 2011). An ample number of studies have revealed that epigenetic modifications play important role in silencing and activation of gene transcription (Velerken, Hurt, and Hollingsworth, 2012).
Because of these roles, processes that disrupt the epigenetic balance in the cell have the effect of initiating the development of cancer through activation of oncogenes and silencing of tumor suppressors (Velerken, Hurt and Hollingsworth,2012). Unusual global epigenetics is a hallmark of cancer (Sharma, Kelly, and Jones, 2010). In contrast to classic genetics, the changes due to epigenetics are reversible (Velerken, Hurt, and Hollingsworth, 2012). This reversibility has been employed in the development of therapeutic drugs and biomarkers to assess the stage or prognosis of cancer.
Today, there is a consensus that epigenetics and genetic alterations are the major factors in the initiation and development of many types of cancers such as breast, colorectal, lung, gastric, and others (Sharma, Kelly, and Jones, 2010). Epigenetics majorly affects the accessibility of chromatin to gene transcription via DNA and nucleosome modification (Lund and Lohuizen, 2004). Currently, the major epigenetic modifications that have been studied include DNA methylation, histone modification, nucleosome positioning, and micro RNA expression. Epigenetic changes occur during cell differentiation and are retained through successive cell division namely mitosis and meiosis (You and Jones, 2012).
The result of changes is that cells with identical genetic features possess unique identification marks. It is the improper heritable transfer of these marks that can lead to inhibition or activation of various signaling elements and ultimately the development of cancer (Sharma, Kelly, and Jones, 2010). In this paper, it will be shown using several examples that epigenetics plays a central role in the development of cancer. The first section of this essay will take a general look at the mechanisms of epigenetics. The rest will give a detailed discussion of some types of cancers before concluding at the end.
Mechanisms of epigenetics
Epigenetics occurs via several signaling pathways. These pathways are regulated in a synergistic way to produce heritable changes at the cellular level. However, some forms of epigenetic modifications work independently to produce either activation or repression on some genes. It is also common for some genes to undergo different epigenetic changes in different types of cancers. Some of the most studied ones are discussed below.
DNA methylation involves the addition of methyl groups at the 5’ end of cytosine in CpG dinucleotide under the influence of DNA methyltransferases namely: DNMT1, DNMT3A, DNMT3B (Rodriguez-Paredes and Esteller, 2011). It is the most studied epigenetic mechanism and plays a role in virtually all types of cancers. DNA methylation is one of the cellular reactions that play a central role in controlling gene activity and nuclear structure (Esteller, 2008).
The addition of the methyl group principally occurs at the CpG rich sites (CpG islands), in gene promoter regions, or repetitive sequences such as centromeres and retrotransposons (Rodriguez-Paredes and Esteller, 2011). DNA methylation results in the silencing of genes and noncoding regions (Rodriguez-Paredes and Esteller, 2011). Some regions of CpG island are methylated but most are not (Rodriguez-Paredes and Esteller, 2011).
Naturally, it occurs to ensure chromosomal stability and as part of development such as silencing of X-chromosomes to ensure monoallelic and genomic imprinting (Rodriguez-Paredes and Esteller, 2011). DNA methylation may confer gene silencing capability as in the case of aberrant methylation of MASPIN (a serum protease inhibitor) and a germline, MAGE gene (Esteller, 2008).
There is a marked disparity in levels of methylation between normal and tumorous tissue cells. Tumorigenic tissues have abnormal levels of DNA methylation compared to normal tissues (Esteller, 2008). Decreased methylation is attributed to hypomethylation of repetitive DNA sequences and demethylation of the coding region (Esteller, 2008). The level of hypomethylation increases as the cancerous lesion progresses. The progression of cancer is aided by activities that follow reduced methylation such as the high likelihood of mutative deletions, translocations, and chromosomal rearrangements (Esteller, 2008). All these changes result in an unstable genomic landscape.
In contrast to general hypomethylation in neoplastic cells, hypermethylation of CpG islands in the promoter region of tumor-suppressors leads to the inactivation of these cells and the proliferation of cancer. For example, hypermethylation of CpG island in the promoter region of the VHL gene leads to the inactivation of the VHL gene (related to Von Hippel-Lindau disease) (Esteller, 2008). This conclusion is based on evidence that hypermethylation affects critical cellular functions such as DNA repair, apoptosis, angiogenesis as well as intercellular interaction which are the major aspects of cancer development (Esteller, 2008).
Histone proteins enclose the DNA forming nucleosome thus shielding the genetic material from the direct influence of the nuclear material. Repeating units of nucleosomes from the chromatin. The structure of chromatin determines how the genetic information is stored in a cell (Sharma, Kelly, and Jones, 2010). The configuration of the chromatin greatly affects the activation or silencing of genes in the nucleus of the cell (Esteller, 2008). A complete nucleosome is comprised of 2 Histone 2A molecules and H3 and H4 dimers.
Each histone protein has protruding N-terminal tails where covalent modifications such as acetylation, methylation, phosphorylation, ubiquitination, and ADB ribosylation occur (Veeck and Esteller, 2010). A closed conformation is formed due to oppositely charged N terminal tails and the DNA (Esteller, 2008). This closed configuration serves to silence some genes as they are rendered out of reach of transcription factors. However, the charges on the N-terminal tails are neutralized by the addition of acetyl group and other organic components resulting in a loose configuration that can be easily transcribed (Taby and Issa, 2010).
Easily accessible genes mean they are within reach of transcription factors and prone to translation. Thus, a previously silenced gene may become activated with unpredictable effects. Apart from acetylation of N-terminal tails of histones, methylation, phosphorylation, ubiquitination, sumoylation, and ADP ribosylation are also possible covalent modification reactions that can occur on the N-terminal tails. These reactions are under the influence of three major enzymes histone
acetyltransferase (HAT), HDAC, histone methyltransferase(HMT), and histone demethylase (HDMT), have the potential to activate or repress various genetic complexes (Taby and Issa, 2010). Others are kinases, phosphatases, ubiquitin ligases and deubiquitinases, SUMO ligases, and proteases (Rodriguez-Paredes and Esteller, 2011). Histones modifications affect several nuclear processes such as gene transcription, DNA repair, DNA replication, and chromosome compaction (Esteller, 2008). This gives a clear picture of how tumor development may arise as these processes are tightly regulated in normal cells.
Studies have revealed a combination of modified histones with/without DNA methylation in some tumor suppressor genes. For example, hypoacetylated and hypermethylated histones H3 and H4 inactivate some tumor suppressors. In addition, some studies have shown loss of histone 4 lysine 16 monoacetylation and histone H4 lysine 20 methylation in cancer development (Taby and Issa, 2010). The above-mentioned histone modifications can result in the activation or suppression of some genes. For example, trimethylation of lysine 4, 36, or 79 on H3 causes gene activation while di or Trimethylation of H3K9 leads to gene inactivation (Rodriguez-Paredes and Esteller, 2011).
The discovery of microRNA continues to elicit a lot of attention in cancer research. This is because studies have revealed they could be significant elements in the initiation and progression of many cancers. Structurally, MicroRNA is short strands of around 20-30 dinucleotides whose combination match those of the 3” end of untranslated mRNA. Noncoding RNA impairs the translation of mRNA by base pairing in the 3’ mRNA untranslated region (Esteller, 2008).
This has the effect of making target genes lose their activity or degrade rapidly. Like any other gene, miRNA can be regulated by epigenetic mechanisms (Sharma, Kelly, and Jones, 2010). Epigenetic studies have found variations in miRNA expression between normal and tumor cells (Esteller, 2008). Like many genes, miRNA are epigenetically regulated at the promoter region of many genes critical in processes such as cell cycle, apoptosis, and differentiation (Taby and Issa, 2010).
In many malignant cells, miRNA are down-regulated. The downregulation is attributed to hypermethylation in the miRNA 5” region. This silencing can lead to the proliferation of tumors such as breast and lung cancer (Taby and Issa, 2010). However, in certain cases, miRNA are upregulated. This is the case in the miR-17-92 cluster associated with lung and breast cancer (Taby and Issa, 2010). A lot of miRNAs continue to be discovered, perhaps, an indication of their relevance in gene maintenance interactions (Dowson and Kouzarides, 2012).
Mirna effects are not localized in any particular region but are part of the complex global epigenetic interaction composed of DNA methylation and histone modification that serve to maintain global gene patterns (Dowson and Kouzarides, 2012; Sharma, Kelly and Jones, 2010).
Mirna can be tumor suppressive or naturally oncogenic depending on the genes they act upon. For example, miRNA 15 and 16 that target BCL2 are downregulated in chronic lymphocytic leukemia. In lung cancer, let 7, a miRNA that targets the oncogene RAS is downregulated (Dowson and Kouzarides, 2012). miRNA modification, just like DNA methylation and histone modification is reversible. Chromatin modifying drugs have been found capable of activating tumor suppressed miRNA(Sharma, Kelly, & Jones, 2010). This development signals future potential applications in anti-cancer drugs.
Nucleosome remodeling and positioning
DNA sequence, chromatin assembly protein, histone variants, post-translational histone modification, and nucleosome remodelers affect the chromatin structure (Sharma, Kelly, and Jones, 2010). Owing to the delicate nature of conformation of chromatin which always needs to be preserved, these events can affect gene expression. Change in nucleosome conformation can be brought about by the replacement of natural histone proteins with variant ones. New conformation of nucleosome may determine whether a DNA sequence is accessible to transcription or not (Sharma, Kelly, and Jones, 2010). A closed-loop means less accessibility while an open plastic confirmation means the DNA will be easily accessible to transcription factors.
The absence of nucleosome at start sites is correlated with gene activation while present at the transcription sites can confer gene repression properties. As explained above, epigenetic changes play key roles in the development of cancer because they are present at the very basic level of the genome. These changes may act together or independently to initiate the development of cancers through activation of oncogenes or inactivation of tumor suppressor genes. In most cases, tumor development arises from a cascade of events involving more than one of these mechanisms.
Specific cancer examples
Cancer development is a result of activation of oncogenic elements and /or inactivation of tumor suppressors. Many cancers are due to genetic defects. However, epigenetics has also been established to be a serious factor in the initiation and progression of many cancers. Carcinogenesis can result when the epigenetic balance is disturbed. In this section, a few epigenetics aspects of some common cancers will be examined.
Prostate cancer(PC) is the leading cause of cancer-related death among men in western countries (Crea, et al., 2012). In the United States, PC produces the second-highest mortality among men from cancerous diseases(Albany, et al., 2011). Unlike other common cancers(lung and colon), the incidence of PC has risen in the past few years (Crea, et al., 2012). Early PC can be treated by surgery, radiation, hormonal therapy, or a combination of these but late PC is generally resistant to any form of treatment (Crea, et al., 2012).
The two main epigenetic mechanisms playing key roles in prostate cancer development are DNA methylation and histone modification (Albany, et al., 2011). Hypermethylation of CpG island is common during neoplastic transformation of prostate cells. Histone modification leads to a change in chromosome structure that alters gene function and transcription (Albany, et al., 2011).
Several studies have found that factors involved in apoptosis, cell cycle, and DNA repair are silenced by DNA methyltransferases in PC (Crea, et al., 2012). Li et al. (2005) carried out a database search that revealed more than 30 genes with unusual hypermethylation in Prostate cancer (Li, Caroll, and Dahiya, 2005). These genes were involved in cellular mechanisms such as hormonal responses, tumor invasion, cell cycle as well as DNA repair (Li, Caroll, and Dahiya, 2005).
The same researchers also found out that dysfunctions in most of these genes are brought about by promoter hypermethylation. Specific functions and genes affected by hypermethylation in prostate cancer include histone methylation (GSTP1, PSA), DNA hypomethylation (CAGE, HPSE, and PLAU), repair of DNA damage (GSTP1, MGMT), cell cycle control (CND2, CDKN2A), histone hypoacetylation (CAGE, HPSE, and PLAU). Each of the above genes shows a varying degree of hypomethylation and effect. For example, hypomethylation of PLAU promoter is associated with increased invasive capacity and tumorigenesis in hormone-independent prostate cancer (Li, Caroll, and Dahiya, 2005). Another gene with high frequency in prostate cancer is CAGE. Hypomethylation of CAGE results in its widespread expression in cancer tissues (Li, Caroll, and Dahiya, 2005)
Hypermethylation in Prostate cancer
Promoter hypermethylation is associated with gene repression and propagation of neoplasm in PC (Crea, et al., 2012). This epigenetic alteration inactivates many tumor suppressor genes tasked with genomic functions such as hormonal signaling, DNA repair, cell adhesion, cell cycle regulation as well as cell apoptosis(Albany, et al., 2011). Interestingly, many suppressors common in other cancers such as PTEN, Rb, and TP53 are not hypermethylated in PC (Albany, et al., 2011).
Of all the transcriptional activators in PC, the androgen receptor (AR) deserves a special mention. AR is a key receptor in the development and progression of PC. Indeed, PC is traditionally treated with androgenic drugs(Albany, et al., 2011). Studies have shown that CpG methylation and histone acetylation play a significant role in the AR pathway signaling (Albany, et al., 2011). This methylation favors the progression of PC.
Hypomethylation in PC
Hypomethylation is a common epigenetic defect observed in PC. It is marked by decreased methylation of repetitive sequences such as LINE1 and retrotransposons(Albany, et al., 2011). Hypomethylation is believed to initiate oncogenesis through mechanisms such as activation of oncogenes (e.g. MYC and H-RAS) and generally bringing about genomic instability (Albany, et al., 2011). Recent investigations have demonstrated a positive relationship between MYC gene overexpression in PC and the progression of cancer (Albany, et al., 2011). PLAU gene has been cited as potentially promoting tumor invasion and metastasis in PC (Albany, et al., 2011).
Some genes linked to prostate cancer are suspected to be under the control of histone modification. For example, decreased coxsackie and adenovirus receptor (CAR) gene expression has been reported in prostate cancer (Li, Caroll, and Dahiya, 2005). This is because CAR is modulated by histone acetylation and was found activated by HDAC inhibitor (Li, Caroll, and Dahiya, 2005). Methylation of Lysine 9 in Histone 3 results in repression of AR gene in PC cell lines and tissues (Albany, et al., 2011).
Histone deacetylase 6 (HDAC6) has a marked effect on AR including its binding, sensitivity, and nuclear localization. Research investigations have shown greater expression of SRC1 and TIF2 genes in patients with advanced PC. This overexpression is a result of the up-regulation of AR co-activators brought about by the action of HDAC6 (Albany, et al., 2011). Global levels of histone modifications are closely linked to the progression of PC and are indicative of the tumor stage, PC antigen levels, and capsule invasion (Albany, et al., 2011).
These changes are even employed to identify cases with H3K4 and H3K18 acetylation being reliable indicators of possible relapse of primary PC (Albany, et al., 2011). These changes portend possible application in the diagnosis of PC. Indeed, some biomarkers based on HDAC have already been developed.
Enhancer of zeste homolog (EZH2), a subunit of polycomb repressive complex 2 (PRC2) is an important gene in PC. EZH2 catalyzes trimethylation of histone 3 on Lysine 27 and is over-expressed in PC (Albany, et al., 2011). EZH2 has a higher expression in metastatic PC (Albany, et al., 2011). EZH2 is believed to promote PC progression and metastasis through its action of epigenetically silencing several tumor suppressors including ADRB2, CDH1, PSP94, and DAB2IP. Another gene, SLIT2, found to inhibit PC cell proliferation and invasion is silenced by EZH2-mediated H3K27 trimethylation (Albany, et al., 2011).
Colorectal cancer (CRC) is one of the most important malignancies in the western world (Engeland, Derks, Smith, Meijer, and Herman, 2011). The initiation and progression of CRS are influenced by both epigenetic and genetic factors (Lao and Grady, 2011). CRC is characterized by marked global DNA hypomethylation in the primary state of carcinogenesis (Engeland, Derks, Smith, Meijer, and Herman, 2011). Unlike most cancers, the hypomethylation is concentrated mostly in the repetitive sequences (e.g. retrotransposons and retroviral agents) termed CpG island shores but is less common in real CpG islands (Engeland, Derks, Smith, Meijer, and Herman, 2011).
Hypomethylation was initially thought to activate CRC oncogenes. However, recent studies have confirmed CRC initiation to be largely an outcome of increased genomic instability for example aberrant recombination and chromosomal replication brought about by these epigenetic changes (Crea, et al., 2012)
Apart from global hypomethylation, an established feature of CRC epigenetics is promoter hypermethylation. Hypermethylation of promoter- CpG island is believed to inactivate tumor suppressors for CRC (Lao and Grady, 2011).
There is evidence hypomethylation induces primary CRC while inhibiting secondary advanced stages (Engeland, Derks, Smith, Meijer, and Herman, 2011). It was found metastasis is preceded by aberrant activation of Insulin-like Growth Factor II (IGF2) by hypomethylation of its promoter region. This results in the activation of the IGF1 receptor leading to further activation of P13K and GRB2/RAS/ERK pathways (Engeland, Derks, Smith, Meijer, and Herman, 2011). Still, the oncogenic role of IGF2 in the development of CRC remains unclear (Engeland, Derks, Smith, Meijer, and Herman, 2011).
An established epigenetic change in CRC is the hypermethylation of the promoter CpG island of putative CRC-suppressors. This methylation also affects a myriad of functions and molecules including TP53, P13K, retinoic acid, IGF signaling, DNA repair as well as cell cycle/transcription regulation (Engeland, Derks, Smith, Meijer, and Herman, 2011). Of particular note is the methylation of mismatch repair gene MLHI. MLHI has been an important gene in elucidating the progression of secondary CRC (Esteller, 2008). The many subsets of CRC with varying patterns of promoter methylation are explained by many factors.
They vary according to age, sex, family history, location in the colon, smoking, as well as MSI/BRA/KRAS mutation(Lao & Grady, 2011). In CRC methyl CpG binding proteins are associated with CRC progression and inactivation of tumor suppressor genes. These methyl-CpG binding proteins bind hypermethylated DNA leading to a closed, DNA-inaccessible chromatin structure. Such methyl CpG island binding proteins include methyl-binding domain(MBD) protein family, Zinc finger protein as well as SET/Ring finger associated proteins (UHRFI and UHFR2) (Lao and Grady, 2011).
miRNA affects several aspects in CRC that contribute to the progression of CRC. In CRC there is a marked global down-regulation of miRNA (Agire, et al., 2009). This effect is associated with hypermethylation as well as histone deacetylation (Agire, et al., 2009). miRNA 141 and miRNA 200 affect epithelial cell differentiation while miRNA 145, 135a, and 135 are involved in WNT signaling (Engeland, Derks, Smith, Meijer, and Herman, 2011).
Mirna 375 and miRNA 520 aid in the migration and invasion of affected cells. Non-coding RNA has also been found to influence CpG island hypermethylation, repressive chromatin configuration, and infiltration by MeCP2 and MBD2 (Engeland, Derks, Smith, Meijer, and Herman, 2011). Epigenetic changes in miRNA include CpG-promoter hypermethylation of miRNA 34b and 34c that target tumor-suppressiveTP53 pathway. In addition, these two noncoding RNA together with miRNA 148a have been associated with metastatic CRC (Engeland, Derks, Smith, Meijer, and Herman, 2011).
Histone acetylation and demethylation are the most studied post-translational histone modifications on CRC. Transcriptionally, inactive genes in CRC are trimethylated in Histone H3 lysine 9 and 27 in contrast to methylation at the H3 lysine inactive genes (Engeland, Derks, Smith, Meijer, and Herman, 2011). This modification spearheads the development and progression of CRC.
Lung cancer is an important health problem that affects and claims millions of lives each year (Bownman, Yang, Semler, and Fong, 2006). According to WHO, lung cancer claims over 1.3 million lives a year(Qiu, Perez-Soler, and Zou, 2011).
The two main subgroups of lung cancer are small-cell lung cancer (SCLC) and non-small cell lung cancer (NSCLS). NSCLS forms the bulk of lung cancer and includes squamous cell carcinoma, adenocarcinoma, and cell carcinoma (Risch and Plass, 2008). Traditionally believed to be brought about by genetic defects, it is now evident that epigenetics plays a significant role in the initiation and progression of lung cancer(Bownman, Yang, Semler, and Fong, 2006). Cigarette smoking accounts for about 80% of lung cancer (Risch and Plass, 2008; Qiu, Perez-Soler, and Zou, 2011).
Lung cancer and DNA methylation
DNA Methylation in lung cancer can be identified at the onset of the tumor development (Risch and Plass, 2008). Several studies have documented promoter hypermethylation in lung cancer. A good example is the promoter methylation and subsequent silencing of tumor suppressor, P16, an event common in the primary stage of tumorigenesis of various cancers including, gastric, colorectal as well as lung tumors (Qiu, Perez-Soler, and Zou, 2011). Similar silencing was found in other genes including Death Associated Protein (DAP), Death Associated Protein Kinase 1 (DAPK1), as well as RASSF1A (Risch and Plass, 2008).
Other is caspase-8, retinoic acid receptor (RARβ), tissue inhibitor of metalloproteinase3 (TIMP3), methyl guanine, DNA, and PTEN. These genes are involved in many cellular processes and have been established to be key players in lung carcinogenesis. Some of the processes they are involved in include DNA repair, cell mobility/adhesion, apoptosis, cell proliferation, as well as cell cycle regulation (Bownman, Yang, Semler, and Fong, 2006).
According to Qiu et al (2011), DNA hypermethylation sets the ground for future inherent mutations due to the general genomic instability it brings about. This is especially likely considering among smoker patients with no small cell lung cancer, there is overexpression of DNA methyltransferases namely DNMT1, DNMT3A, and DNMT3B (Qiu, Perez-Soler, and Zou, 2011). Past studies have shown defective methylation of the CpG site facilitates the adhesion of cigarette smoke carcinogens(Risch & Plass, 2008). These carcinogens are responsible for widespread DNA damage in human lung cancer cells. The carcinogens also increase the rate of mutation in tumor suppressor genes of lung cancer such as P53.
A higher occurrence of methylation has been found in p16, MGMT, RASSF1, MTHFR, and FHIT genes in lung adenocarcinoma and squamous cell carcinoma (Qiu, Perez-Soler, and Zou, 2011). DNA methylation has also proved a reliable marker for early diagnosis and detection of lung cancer (Qiu, Perez-Soler, and Zou, 2011). P16INK4a and MGMT promoter methylation has been used to predict the development of squamous cell carcinoma (Qiu, Perez-Soler, and Zou, 2011).
Like many other cancers, lung cancer is characterized by global hypomethylation. The loss of methylation is centered on the repetitive regions of the genome and in specific sites of genes. The latter results in alteration of gene expression whereby a gene may either be inactivated or activated. A study of bronchial epithelial cells (NHBE) in lung cancer has revealed loss of methylation (Bownman, Yang, Semler, and Fong, 2006).
Bowman et al. correlated aberrant hypermethylation with downregulation of tumor suppressors (P16, FHIT, Rb, VHL, GSTP1, DAPK, and MGMT) in samples from lung cancer tissues (Bownman, Yang, Semler, and Fong, 2006). These findings corroborate others that have found different levels of methylation in subtypes of lung cancer and related cells such as TSLCI, CDH13, Hsrbc, SPARC as well as DBCI. DNA methylation affects genes involved in hallmarks of cancer initiation and progression including cell cycle regulation (p16), DNA repair(MGMT), RAS signaling (RASSF1A), and invasion (cadherin, TIMP3) (Bownman, Yang, Semler, and Fong, 2006).
Alterations in histone proteins and chromatin enzymes have been found in lung cancer. Past studies have shown adjusted global capacity of histone 3 lysine 4 dimethylation (H3K4diME), histone 3 lysine 9 acetylation (H3K9AC), and histone 2A lysine 5 acetylation (Qiu, Perez-Soler, and Zou, 2011). HDAC plays a key role in m tumorigenesis of lung cancer (Bownman, Yang, Semler, and Fong, 2006). HDAC3 was found upregulated in squamous cells from lung cancer patients suggesting HDAC blocks critical tumor repressor pathways that protect against lung cancers (Bownman, Yang, Semler, and Fong, 2006).
Some histone compounds have been discovered to indicate a possible survival rate for lung cancer patients. In this regard, lower levels of H3K4diME and H3K18Ac have indicated a low survival rate for a lung cancer patient (Qiu, Perez-Soler, and Zou, 2011). Various histone modification compounds have proved indicative of the progression of lung cancer. Poor prognosis has been associated with decreased HDAC (class II) gene while HDAC3 has been found upregulated in squamous lung cancer compared to normal lung cells. These findings add credence to the suggestion that histone modification plays a significant role in the initiation and progression of lung cancer. Due to their reversibility, epigenetic changes present a possible avenue for a therapeutic approach against cancer.
Defective expression of miRNA has been found in lung cancer. MiR-22, -126, -131, -519, -133B, -159, -16 and -183 have been found be part of oncogenic processes including cell proliferation, migration, and invasion(Qiu, Perez-Soler, and Zou, 2011). miRNA profiles in human lung cancer have also found a new area of application; that of diagnosis and prognosis (Qiu, Perez-Soler, and Zou, 2011). Ha-miR-205 has been labeled a potential marker for squamous carcinoma. As miRNA is a relatively new aspect of epigenetics, the future investigation will be relied on to present a better picture and roles these elements play in overall carcinogenesis.
Breast cancers are the leading cause of cancer death among women worldwide (Vo and Millis, 2012). Incidences of breast cancers vary across continents but are much higher in western countries (Veeck and Esteller, 2010). Apart from long-established genetic causes, epigenetic mechanisms are increasingly gaining recognition as significant players in the development of breast cancer (Vo and Millis, 2012; Veeck and Esteller, 2010; Radpour, et al., 2011). DNA methylation, histone modification, and miRNA are the major epigenetics aspects involved in the development of breast cancers.
Global DNA hypomethylation is much greater in breast cancer than in many other solid tumors (Veeck and Esteller, 2010). About 50% of breast cancer show reduced methylation compared to normal tissues (Veeck and Esteller, 2010). DNA hypomethylation has been associated with several effects in breast tumors. Reduced methylation especially in transposable elements contributes to genomic instability brought about by transcription reactivation and relocation of DNA elements within the genome (Veeck and Esteller, 2010). Unlike ovarian cancer, DNA hypomethylation in breast cancer is associated with primary tumor development.
Hypomethylation in breast cancer also directly affects individual genes (Veeck & Esteller, 2010). For example, the MAGE gene is methylated and silenced in mature tissues with breast cancer cells. Similar hypomethylation is observed in PLAU, SNCh, and MDR1 genes(Veeck & Esteller, 2010). Hypermethylation of CpG island is common in breast cancer. Several genes are silenced through this form of methylation including ER (necessary for growth), HOXA5 (hinders apoptosis), E-cadherin (protects against invasion and metastasis) as well as RARbeta (cell proliferation)(Vo & Millis, 2012). DNMTs are over-expressed in many cancers including breast cancer.
Recent studies have revealed levels of DNMT3b that are 30% higher compared to normal breast tissue. This rise is suspected to play a role in interfering with the normal DNA methylation process (Veeck and Esteller, 2010). The overexpression of DNMT3b has been associated with higher tumor grade, loss of estrogen receptor, and up regulation of K67, a proliferation biomarker (Veeck and Esteller, 2010). This is evidence that DNMT3b plays a role in breast cancer progression and metastasis (Veeck and Esteller, 2010). In primary state of breast cancer, expression of HDAC is linked to expression of estrogen receptor (ER) and progesterone receptor (Veeck and Esteller, 2010).
Estrogens and Estrogen Receptors
Estrogen hormones are recognized as the major catalysts of breast cancer (Vo and Millis, 2012). The activities of Estrogen are connected to their receptor termed estrogen receptors that include ERα and ERβ coded by ESR1 and ESR2 genes respectively (Veeck and Esteller, 2010). ER has the ability to assume various homo and heterodimer conformations when activated by appropriate molecules (Vo and Millis, 2012). New configurations of ER enable the receptors involvement in many genomic regulatory pathways. Thus the receptor can act as a transcription factor for various genes. Studies have suggested increased risk of cancer development form transcription mediated by ERα (Vo and Millis, 2012).
The type of ER affects the nature of breast cancer in women. ERα is the most common receptor in women diagnosed with breast cancer and account for about 75% of all positive diagnosis cases and better prognosis (Vo and Millis, 2012). On the other hand, women with breast tumor but lacking ERα have shown poor prognosis and greater malignancy of the tumor (Vo and Millis, 2012). Aberrant methylation of CpG island has been linked to the loss of expression of ERα (Vo and Millis, 2012).
Non coding RNA
MiRNA are significant in progression of breast cancer. MiRNA are downregulated in breast cancer just like in many other cancer types. MiRNA are being explored as possible biomarkers for early detection of breast cancer (Radpour, et al., 2011).Over expression of miR 221 and MiRNA 222 has been associated with post translational suppression of ERα and tumor suppressors including CDKN1B, CDKN1C, BIM, PTEN, TIMP3 and FOXO3 (Vo and Millis, 2012). Apart from potentially having applicable biomarking properties, some miRNA have displayed some tumor suppressive properties. Radpour et.al (2011) found miR-152 exerted some inhibitory effects on SKBR3, a group of non- aggressive breast cancer cell line (Radpour, et al., 2011).
Estrogen receptor influences transcription through its interaction with HAT and histone lysine specific demethylase, JMJD2B (Vo and Millis, 2012). This interaction attracts ATP remodeling complexes and his tone enzymes to gene promoters resulting in rapid cell division that can transform into tumor growth (Vo and Millis, 2012).
Epigenetic changes are important in the initiation and development of many cancers. This modifications occur at the gene level inside the chromatin and have the potential to alter the configuration and chemistry of genetic matter. The most studied epigenetic mechanisms to date are DNA methylation, post-translational histone modification, non-codingRNA (miRNA) and nucleosomal positioning. Each of these mechanisms may act alone to influence gene expression.
However, this is rare and all may interact to bring about changes in gene expression. Together with classical genetic aberrations, epigenetics leads to fundamental changes at genome level. These changes affect important cellular processes such as cell cycle regulation, DNA repair, apoptosis and proliferation. Epigenetic changes disturb genomic balance and may bring about activation and/or deactivation of genes. In this respect, tumor development occurs when an oncogene is activated or when tumor suppressors are deactivated. In many types of cancers for example, gastric, prostate, colorectal, lung and breast the role of epigenetics is clearly evident.
In breast cancer there is hypermethylation of CpG island in key genes namely; BRAC1, E-cadherin, TMSI and hormonal estrogen receptor. There is also a marked global genomic hypomethylation. In lung cancer, CpG hypermethylation of P16, DAPK and RASSF1A, global genomic hypomethylation and deletion of CBP and BRGI genes are key factors. On the other hand, hypermethylation of GSTP1 promoter, gene amplification of polycomb histone methyltranferase gene, EZH2 and covalent modification of histone H3 and H4 stand out in prostate cancer. Each of these examples also displays aberrations in miRNA expression.
These examples reinforce the important role epigenetics can play in development of many cancers. Apart from being initiators of many cancers, epigenetic changes and modifications are increasingly being utilized in development of diagnostic biomarkers. These biomarkers will be crucial in identification and treatment of many types of cancers. It should be noted that owing to the intricate nature of gene interactions, many effects of epigenetics remain inconclusive. However, with more investigation currently underway in this area, a lot will be revealed in near future. A clear understanding of epigenetic role in cancer will result in better prognosis and intervention strategies.
Agire, B. E., Ramirez, B., Roman-Gomez, Z., Prosper, J., Foncillas, G., Fonceca, m. R., et al. (2009). Epigenetic regulation of microRNA expression in colorectal cancer. Int J or Cancer, 12(3), 390-397.
Albany, C., Alva, A. S., Aparicio, A. M., Singal, R., Yellapragada, S., Sonpavde, G., et al. (2011). Epigenetics in prostate cancer. Prostate Cancer, 20(11). Web.
Bownman, R. V., Yang, I. A., Semler, A. B., & Fong, K. M. (2006). Epigenetics of cancer. Respirology, 11. Web.
Crea, F., Sun, L., Mai, A., Chiang, Y. T., Farrar, W. L., Danesi, R., et al. (2012). Emerging role of histone lysine demethylases in prostate cancer. Molecular Cancer, 11, 51-66.
Dowson, M. A., & Kouzarides, T. (2012). Cancer epigenetics:from mechanism totherapy. Cell, 12. Web.
Engeland, M. v., Derks, S., Smith, K. M., Meijer, G. A., & Herman, J. G. (2011). Colorectral cancer epigenetics: Complex simplicity. Oncology and Dev Biology, 29(11). Web.
Esteller, M. (2008). Epigenetics in cancer. N Eng J Md, 358, 1148-59.
Lao, V. V., & Grady, W. M. (2011). Epigenetics and Colorectal Cancer. Nat Rev Gastroenterol Hepatol., 8(12), 686-700. Web.
Li, L.-C., Caroll, P. R., & Dahiya, R. (2005). Epigenetic changes in prostrate cancer: Implication for diagnosis and treatment. J of the National Can Instiutue, 97(2). Web.
Lund, A. H., & Lohuizen, M. v. (2004). Epigenetics and cancer. Genes Dev., 18, 2315-2335. Web.
Qiu, X., Perez-Soler, R., & Zou, Y. (2011). Epigenetic control of tumor suppressor genes in lung cancer. Web.
Radpour, R., Barekati, Z., Kohler, C., Schumacher, M. M., Grussenmeyer, T., Jenoe, P., et al. (2011). Investigations of targeted genes ,microRNA and proteins upon demethylation treatment. Plos ONE, 6(11), e27355. Web.
Risch, A., & Plass, C. (2008). Lung cancer epigenetics and genetics. Int. J. Cancer, 123, 1-7. Web.
Rodriguez-Paredes, M., & Esteller, M. (2011). Cancer epigenetics reaches mainstream oncology. Nature Medicine, 17(3). Web.
Sharma, S., Kelly, T. K., & Jones, P. A. (2010). Epigenetics in cancer. Carcinogenesis, 1, 27-36. Web.
Taby, R., & Issa, J.-P. J. (2010). Cancer epigenetics. CA Cancer J Clin, 60, 376-392. Web.
Veeck, J., & Esteller, M. (2010). Breast cancer epigenetics: from DNA methylation to microRNAs. J Mammary Gland Bio Neoplasia, 15(1), 5-17. Web.
Velerken, L.E., Hurt, E.M., & Hollingsworth, R.E (2012). Role of epigenetics regulation in stem cells and cancer biology. J Mol Med. Web.
Vo, A. T., & Millis, R. M. (2012). Epigenetics and breast cancer. Obstetrics and Gynecology International, 20(12), 323-746. Web.
You, J. S., & Jones, P. A. (2012). Cancer genetics and epigenetics: Two sides of the same coin? Cancer Cell, 22(1), 9-20. Web.