Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.1.1.37 (DNA methyltransferase)
 4,983 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Anomalous expression of certain types of mucins occurs in pancreatic tumors, but little is known about the causes. MUC2 and MUC5AC are not expressed in normal pancreas. In the present study an immunohistochemical screening showed that MUC2 antigen was expressed in 6% of invasive tumors. Of the pancreatic cell lines, 2.4% expressed MUC2 message and antigen. In contrast, MUC5AC antigen was expressed in 86-100% of invasive adenocarcinoma (depending on the antibody). MUC5AC message and antigen were expressed in 66.7% of the cell lines tested. A polymerase chain reaction based assay was used to determine if methylation of CpG sites immediately 5' of the transcription initiation sites of the MUC2 and MUC5AC genes could be related to mucin expression in the cell lines. Digestibility by the methylation sensitive restriction enzyme HpaII correlated with the presence or absence of mRNA in 100% and 77.8% of the cell lines for MUC2 and MUC5AC, respectively. Treatment of a cell line that did not express MUC2 or MUC5AC gene products with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine resulted in an increase in MUC2 message but no change in MUC5AC message. In summary, the expression of MUC2 gene products correlated well with methylation of the proximal region of the promoter whereas expression of MUC5AC may involve additional regions or other mechanisms.
 ...
PMID:Methylation status of promoters and expression of MUC2 and MUC5AC mucins in pancreatic cancer cells. 1252 22

Mucins are highly glycosylated proteins that play important roles in carcinogenesis. In pancreatic neoplasia, MUC2 mucin has been demonstrated as a tumor suppressor and we have reported that MUC2 is a favorable prognostic factor. Regulation of MUC2 gene expression is known to be controlled by DNA methylation, but the role of histone modification for MUC2 gene expression has yet to be clarified. Herein, we provide the first report that the histone H3 modification of the MUC2 promoter region regulates MUC2 gene expression. To investigate the histone modification and DNA methylation of the promoter region of the MUC2 gene, we treated 2 human pancreatic cancer cell lines, PANC1 (MUC2-negative) and BxPC3 (MUC2-positive) with the DNA methyltransferase inhibitor 5-azacytidine (5-aza), the histone deacetylase inhibitor trichostatin A (TSA), and a combination of these agents. The DNA methylation level of PANC1 cells was decreased by all 3 treatments, whereas histone H3-K4/K9 methylation and H3-K9/K27 acetylation in PANC1 cells was changed to the level in BxPC3 cells by treatment with TSA alone and with the 5-aza/TSA combination. The expression level of MUC2 mRNA in PANC1 cells exhibited a definite increase when treated with TSA and 5-aza/TSA, whereas 5-aza alone induced only a slight increase. Our results suggest that histone H3 modification in the 5' flanking region play an important role in MUC2 gene expression, possibly affecting DNA methylation. An understanding of these intimately correlated epigenetic changes may be of importance for predicting the outcome of patients with pancreatic neoplasms.
 ...
PMID:MUC2 expression is regulated by histone H3 modification and DNA methylation in pancreatic cancer. 1672 89

A balance between co-inhibitory and co-stimulatory signals in the tumor microenvironment (TME) is critical to suppress tumor development and progression, primarily via maintaining effective immunosurveillance. Aberrant expression of immune checkpoints (ICs), including programmed cell death protein 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), lymphocyte-activation gene 3 (LAG-3) and T cell immunoreceptor with Ig and ITIM domains (TIGIT), can create an immune-subversive environment, which helps tumor cells to evade immune destruction. Recent studies showed that epigenetic modifications play critical roles in regulating the expression of ICs and their ligands in the TME. Reports showed that the promoter regions of genes encoding ICs/IC ligands can undergo inherent epigenetic alterations, such as DNA methylation and histone modifications (acetylation and methylation). These epigenetic aberrations can significantly contribute to the transcriptomic upregulation of ICs and their ligands. Epigenetic therapeutics, including DNA methyltransferase and histone deacetylase inhibitors, can be used to revert these epigenetic anomalies acquired during the progression of disease. These discoveries have established a promising therapeutic modality utilizing the combination of epigenetic and immunotherapeutic agents to restore the physiological epigenetic profile and to re-establish potent host immunosurveillance mechanisms. In this review, we highlight the roles of epigenetic modifications on the upregulation of ICs, focusing on tumor development, and progression. We discuss therapeutic approaches of epigenetic modifiers, including clinical trials in various cancer settings and their impact on current and future anti-cancer therapies.
 ...
PMID:Role of Epigenetic Modifications in Inhibitory Immune Checkpoints in Cancer Development and Progression. 3276 Apr