Epigenetic Modifications: Therapeutic Potential in Cancer

Epigenetic modifications and alterations in chromatin structure and function contribute to the cumulative changes observed as normal cells undergo malignant transformation. These modifications and enzymes (DNA methyltransferases, histone deacetylases, histone methyltransferases, and demethylases) related to them have been deeply studied to develop new drugs, epigenome-targeted therapies and new diagnostic tools. Epigenetic modifiers aim to restore normal epigenetic modification patterns through the inhibition of epigenetic modifier enzymes. Four of them (azacitidine, decitabine, vorinostat and romidepsin) are approved by the U.S. Food and Drug Administration. This article provides an overview about the known functional roles of epigenetic enzymes in cancer development

Developmental methylation of the regulatory region of HoxB5 gene in mouse correlates with its tissue-specific expression

We have studied the dynamics of de novo CpG methylation in the regulatory region of one of the homeobox gene HoxB5 during mouse development by sodium bisulfite sequencing. Methylation pattern was examined at embryonic day 18.5 and adult in kidney and spleen while in the liver the same exercise has been done in 11.5 dpc, 18.5 dpc, 5 dpp and in adult. In the liver at 11.5 dpc, all the 47 contiguous sites (including a CpG island from 2035 to 2330 bp) at 5' regulatory region of HoxB5 were unmethylated. Random methylation commences from 18.5 dpc and continues in 5 dpp and in the adult. In the kidney at 18.5 dpc, 26 CpGs were examined (excluding the CpG island region) and all of them were unmethylated but the fetal spleen had at least a few sites considerably methylated. In the adult there was a low level methylation in the kidney, on the other hand, in the spleen, all the CpGs were methylated except a few sites and certain sites were totally methylated. Thus in the adult, the level of methylation was much higher than in the fetal stage. On the other hand semi-quantitative RT-PCR revealed that the extent of expression of HoxB5 was higher in embryonic stages than in the adult. Thus HoxB5 is a good paradigm to support that the developmental methylation of HoxB5 and its expression pattern show an inverse correlation

HOXA9 and SOX1 - a promising DNA methylation based diagnostic biomarker for epithelial ovarian cancer

Epigenetic alterations play a major role in cancer. Transcriptional silencing by CpG island hypermethylation is a potential mechanism for the inactivation of tumor related genes. Aberrant DNA methylation patterns might be used as a biomarker for diagnosis and management of cancer patients. Ovarian cancer is characterized by few early symptoms, presentation of the disease at late stage and resulting poor survival. At present, no single epigenetic biomarker is able to accurately detect early ovarian cancer in either tissue or body fluid. Analysis of the methylation status of multiple genes simultaneously in a blood based assay may provide a more sensitive and specific method for the molecular classification and diagnosis of ovarian cancer. To develop a potential, DNA methylation based screening assay for early diagnosis of ovarian cancer, we quantitatively assessed the promoter methylation of HOXA9 and SOX1 gene in 54 ovarian cancer and 18 non neoplastic ovarian specimens by means of a high throughput quantitative, real time PCR based technique (MethyLight). We identified DNA methylation of HOXA9 and SOX1 to be the best discriminator between cancer and non-neoplastic tissue. The gene methylation achieved 93.47% and 78.26% sensitivity for HOXA9 and SOX1, respectively when analyzed in singleplex assay. However the sensitivity increased to 95.92% in the multiplex assay when either or both of the HOXA9 and SOX1 gene promoters showed methylation thereby indicating that these genes appear to have great potential to be evaluated for their methylation level in cell-free DNA or serum DNA as a non-invasive diagnostic marker the early diagnosis of ovarian cancer

Developmental methylation of the coding region of c-fos occurs perinatally, stepwise and sequentially in the liver of laboratory mouse

We have studied the dynamics of de novo DNA methylation of 16 contiguous CpGs in the non-CpG island-coding region of the proto-oncogene c-fos during mouse development by Na-bisulfite sequencing. Methylation commences from 16.5 dpc and occurs in stepwise-manner. In liver 7 sites are methylated between 16.5 dpc and day 5 after birth, but all the sites are completely methylated on 20 dpp and remain so in the adult liver. The present study provides evidence that (1) pattern of methylation of c-fos is distinct from those DNA sequences which methylate pre- and post-implantation, both in terms of the timing and spreading, and (2) spacing of CpGs is an important factor in determining the course of methylation. We suggest that there could be other isoforms of Dnmtases for the c-fos like embryonic genes, not only because they methylate later in development but also because of the difference in kinetics of the reaction, and that the nucleation of certain methylated sites facilitate methylation of neighbouring sites and their maintenance in subsequent cell generations

Biomarkers towards Ovarian Cancer Diagnostics: Present and Future Prospects

ABSTRACT Ovarian carcinoma accounts for highest mortality of all gynecologic malignancies as the disease is asymptomatic until late stages. Biomarkers such as CA-125 and HE4 are being currently used for diagnosis of ovarian cancer, but they show contradicting diagnostic accuracy. Therefore other biomarkers have been investigated for early detection of this disease, but no success has been obtained and no test has yet been recommended for screening a general population. In this instance, aptamers can be effectively used to identify tumor-specific antigens for early diagnosis and targeted therapy of ovarian cancer. This article provides an overview of the biomarkers/panels being explored as well as the potential of aptamers to improve current long-term survival rates of ovarian cancer

Not Available

Not AvailableNot AvailableNot Availabl

Not Available

Not AvailableNot AvailableNot Availabl