Cancer Epigenetics

Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
CA A Cancer Journal for Clinicians (Impact Factor: 115.84). 10/2010; 60(6):376-92. DOI: 10.3322/caac.20085
Source: PubMed


Epigenetics refers to stable alterations in gene expression with no underlying modifications in the genetic sequence and is best exemplified by differentiation, in which multiple cell types diverge physiologically despite a common genetic code. Interest in this area of science has grown over the past decades, especially since it was found to play a major role in physiologic phenomena such as embryogenesis, imprinting, and X chromosome inactivation, and in disease states such as cancer. The latter had been previously thought of as a disease with an exclusive genetic etiology. However, recent data have demonstrated that the complexity of human carcinogenesis cannot be accounted for by genetic alterations alone, but also involves epigenetic changes in processes such as DNA methylation, histone modifications, and microRNA expression. In turn, these molecular alterations lead to permanent changes in the expression of genes that regulate the neoplastic phenotype, such as cellular growth and invasiveness. Targeting epigenetic modifiers has been referred to as epigenetic therapy. The success of this approach in hematopoietic malignancies validates the importance of epigenetic alterations in cancer, not only at the therapeutic level but also with regard to prevention, diagnosis, risk stratification, and prognosis.

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Available from: Jean-Pierre Issa, Nov 24, 2014
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    • "The miRNAs specific binding to complementary sequences of mRNAs may either RISC induces mRNA degradation (perfect pairings) or the translation into protein is blocked (imperfect miRNA-mRNA target pairing) was defined by Watson-Crick base pairing between positions 2 to 8 from the 5'miRNA (also known as the seed) with the 3'untranslated region (UTR) of their target mRNAs (Ghildiyal and Zamore, 2009; Bartel, 2009). The formed miRNA with RISC are then transported back into the nucleus to exert its biological effect since a single miRNA is capable of targeting hundreds of mRNAs, which highlights the impact of gene regulation system in cellular functions (Taby and Issa, 2010). The complementary passenger strand (miRNA*), which was initially thought to be degraded and known as a nonfunctional bioproduct of miRNA biogenesis (Gregory et al., 2005), has recently become an interesting revelation "
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    ABSTRACT: MicroRNAs (miRNAs) are short non-coding RNAs of 20-24 nucleotides that play important roles in carcinogenesis. Accordingly, miRNAs control numerous cancer-relevant biological events such as cell proliferation, cell cycle control, metabolism and apoptosis. In this review, we summarize the current knowledge and concepts concerning the biogenesis of miRNAs, miRNA roles in cancer and their potential as biomarkers for cancer diagnosis and prognosis including the regulation of key cancer-related pathways, such as cell cycle control and miRNA dysregulation. Moreover, microRNA molecules are already receiving the attention of world researchers as therapeutic targets and agents. Therefore, in-depth knowledge of microRNAs has the potential not only to identify their roles in cancer, but also to exploit them as potential biomarkers for cancer diagnosis and identify therapeutic targets for new drug discovery.
    Full-text · Article · Oct 2014 · Asian Pacific journal of cancer prevention: APJCP
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    • "The Dark Side of Epigenetics: Carcinogenesis and Resistance While epigenetics is an exploitable anticancer mechanism, the plasticity of epigenetic changes, with subsequent molecular alterations that regulate the neoplastic phenotype, contributes to carcinogenesis, tumor promotion, chemoresistance, and radioresistance as much as or more than genetic variability [2]. In particular, the yin of epigenetic silencing of tumor suppressor genes is an important mechanism for carcinogenesis. "
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    ABSTRACT: In cancer chemotherapy, one axiom, which has practically solidified into dogma, is that acquired resistance to antitumor agents or regimens, nearly inevitable in all patients with metastatic disease, remains unalterable and irreversible, rendering therapeutic rechallenge futile. However, the introduction of epigenetic therapies, including histone deacetylase inhibitors (HDACis) and DNA methyltransferase inhibitors (DNMTIs), provides oncologists, like computer programmers, with new techniques to “overwrite” the modifiable software pattern of gene expression in tumors and challenge the “one and done” treatment prescription. Taking the epigenetic code-as-software analogy a step further, if chemoresistance is the product of multiple nongenetic alterations, which develop and accumulate over time in response to treatment, then the possibility to hack or tweak the operating system and fall back on a “system restore” or “undo” feature, like the arrow icon in the Windows XP toolbar, reconfiguring the tumor to its baseline nonresistant state, holds tremendous promise for turning advanced, metastatic cancer from a fatal disease into a chronic, livable condition. This review aims 1) to explore the potential mechanisms by which a group of small molecule agents including HDACis (entinostat and vorinostat), DNMTIs (decitabine and 5-azacytidine), and redox modulators (RRx-001) may reprogram the tumor microenvironment from a refractory to a nonrefractory state, 2) highlight some recent findings, and 3) discuss whether the current “once burned forever spurned” paradigm in the treatment of metastatic disease should be revised to promote active resensitization attempts with formerly failed chemotherapies.
    Full-text · Article · Oct 2014 · Translational oncology
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    • "Genome-wide association studies of bladder cancer identified single-nucleotide polymorphisms (SNPs) on chromosome 8q24, upstream of the MYC oncogene, on chromosome 3q28 near the TP63 tumor suppressor gene [5], and in the PSCA gene to be associated with bladder cancer risk [6]. DNA methylation is one of the most consistent epigenetic changes occurring in human cancers [7, 8]. And it is well established that aberrant hypermethylation of the promoter region of tumor suppressor genes is associated with transcriptional silencing, and that hypermethylation is an alternative mechanism of functional inactivation [9] Moreover, promoter hypermethylation of tumor-related gene has also been proposed as a novel biomarker for detecting cancer and predicting prognosis [10]. "
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    ABSTRACT: Bladder cancer is one of the most common cancers worldwide. Fibulin-1, a multi-functional extracellular matrix protein, has been demonstrated to be involved in many kinds of cancers, while its function in bladder cancer remains unclear. So here we investigated the expression and function of fibulin-1 in Bladder cancer. We used real-time PCR, Western blot analysis and immunohistochemistry to determine the expression of fibulin-1 in Bladder cancer cells and patient tissues respectively. Methylation-specific PCR and quantitative sequencing were used to examine the methylation status of FBLN1 gene promoter. Eukaryotic expression plasmid and lentiviral vector were used to overexpress fibulin-1 in Bladder cancer cells 5637, HT-1376 to investigate its function in vitro and in vivo. We identified that fibulin-1 was significantly down-regulated in bladder cancer, and its dysregulation was associated with non-muscle-invasive bladder cancer (NMIBC) grade and recurrence. The promoter region of FBLN1 was generally methylated in bladder cancer cell lines and tissues, further investigation in patient tissues showed that the methylation status was associated with the fibulin-1 expression. Overexpression of fibulin-1 significantly suppressed tumor growth, induced tumor cell apoptosis, decreased cell motility, and inhibited angiogenesis in cultured bladder cancer cells and xenograft tumor in nude mice. Altogether, our results indicated that fibulin-1 expression is associated with NMIBC grade and recurrence, it is epigenetically down-regulated and functions as a tumor suppressor gene and angiogenesis inhibitor in bladder cancer.
    Full-text · Article · Sep 2014 · BMC Cancer
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