trichostatin-a and Carcinogenesis

Primary hyperparathyroidism (PHPT) results from the hypersecretion of parathyroid hormone from parathyroid tumors. A transcription factor, namely Paired box1 (PAX1), is active in parathyroid gland development.. We aimed to study potential epigenetic-mediated mechanism of PAX1 gene in sporadic parathyroid adenomas.. In parathyroid adenomas tissues, we analyzed the DNA methylation via bisulfite-specific polymerase chain reaction (BSP) and histone modifications via chromatin immunoprecipitation in regulating the differential expression of PAX1.. The results showed that mRNA and protein expression of PAX1 was significantly reduced in parathyroid adenomas. Bisulfite sequencing demonstrated hypermethylation in the promoter region of PAX1 (35%; 14/40) and lower levels of histone 3 lysine 9 acetylation (H3K9ac) were observed on the promoter region of PAX1 (6-fold; P < .004) in parathyroid adenomas. Furthermore, upon treatment with a pharmacologic inhibitor, namely 5'aza-2 deoxycytidine, in rat parathyroid continuous cells, we found re-expression of PAX1 gene.. Our study not only reveals expression of PAX1 is epigenetically deregulated but also paves a way for clinical and therapeutic implications in patients with PHPT.

Topics: Acetylation; Adenoma; Adolescent; Adult; Aged; Animals; Carcinogenesis; Case-Control Studies; Cell Line, Tumor; Decitabine; DNA Methylation; Epigenesis, Genetic; Female; Gene Expression Regulation, Neoplastic; Healthy Volunteers; Histone Code; Humans; Hydroxamic Acids; Male; Middle Aged; Paired Box Transcription Factors; Parathyroid Glands; Parathyroid Neoplasms; Parathyroidectomy; Promoter Regions, Genetic; Rats; Young Adult

Colorectal cancer (CRC) is known to be the third most common cancer disease and the fourth-leading cause of cancer-related deaths worldwide. Bile acid, especially deoxycholic acid and lithocholic acid, were revealed to play an important role during carcinogenesis of CRC. In this study, we found organic solute transporter

Topics: Acetylation; Carcinogenesis; Cholera Toxin; Colorectal Neoplasms; Down-Regulation; E1A-Associated p300 Protein; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Histones; HT29 Cells; Humans; Hydroxamic Acids; Membrane Transport Proteins; Promoter Regions, Genetic; RNA, Small Interfering; Up-Regulation

The therapeutic effects of simvastatin for renal cell carcinoma (RCC) are controversial. In this study, the effects of simvastatin on the carcinogenic properties of 3-methylcholanthrene (3MC; an aryl-hydrocarbon receptor [AhR] agonist) in human renal epithelial cells (hRECs) were investigated. We exposed in vitro and in vivo models to 3MC to induce RCC onset. 3MC upregulated the epithelial-mesenchymal transition (EMT) and tumor biomarkers; the models exhibited the reciprocal expression of histone deacetylase 1 (HDAC1) and RhoA, namely increased HDAC1 and decreased RhoA expression, through hypoxia-inducible-factor (HIF)- and AhR-dependent mechanisms. In addition to inducing EMT biomarkers, 3MC decreased von Hippel-Lindau protein levels (a risk factor for RCC) and increased CD44 expression in hRECs, which were reversed by digoxin (a HIF inhibitor) and HDAC inhibitors (suberoylanilide hydroxamic acid and trichostatin A [TSA]). Simvastatin abolished the detrimental effects of 3MC by reducing HDAC1 expression, with resulting RhoA upregulation, and reactivating RhoA in vitro and in vivo. Notably, the protective effects of simvastatin were negated by an HDAC activator (ITSA) through TSA suppression. The crucial role of RhoA in RCC carcinogenesis was verified by the overexpression of constitutively active RhoA. Collectively, these results demonstrate that simvastatin restores RhoA function through HDAC1 inhibition; therefore, simvastatin might serve as adjunct therapy for RCC induced by 3MC.

Topics: Carcinogenesis; Cells, Cultured; Epithelial Cells; Epithelial-Mesenchymal Transition; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Humans; Hyaluronan Receptors; Hydroxamic Acids; Kidney; Methylcholanthrene; Receptors, Aryl Hydrocarbon; rhoA GTP-Binding Protein; Simvastatin

PTPRD (protein tyrosine phosphatase, receptor type, D) is a tumor suppressor gene, frequently inactivated through deletions or epigenetic mechanisms in several cancers with importance for global health. In this study, we provide new and functionally integrated evidence on genetic and epigenetic alterations of PTPRD gene in hepatocellular carcinomas (HCCs). Importantly, HCC is the sixth most common malignancy and the third most common cause of cancer-related mortality worldwide. We used a high throughput single nucleotide polymorphism (SNP) microarray assay (Affymetrix, 10K2.0 Assay) covering the whole genome to screen an extensive panel of HCC cell lines (N=14 in total) to detect DNA copy number changes. PTPRD expression was determined in human HCCs by Q-RT-PCR and immunohistochemistry. Promoter hypermethylation was assessed by combined bisulfite restriction analysis (COBRA). DNA methyl transferase inhibitor 5-azacytidine (5-AzaC) and/or histone deacetylase inhibitor Trichostain A (TSA) were used to restore the expression. We identified homozygous deletions in Mahlavu and SNU475 cells, in the 5'UTR and coding regions, respectively. PTPRD mRNA expression was downregulated in 78.5% of cell lines and 82.6% of primary HCCs. PTPRD protein expression was also found to be lost or reduced in HCC tumor tissues. We found promoter hypermethylation in 22.2% of the paired HCC samples and restored PTPRD expression by 5-AzaC and/or TSA treatments. In conclusion, PTPRD is homozygously deleted and epigenetically downregulated in HCCs. We hypothesize PTPRD as a tumor suppressor candidate and potential cancer biomarker in human HCCs. This hypothesis is consistent with compelling evidences in other organ systems, as discussed in this article. Further functional assays in larger samples may ascertain the contribution of PTPRD to hepatocarcinogenesis in greater detail, not to forget its broader importance for diagnostic medicine and the emerging field of personalized medicine in oncology.

Topics: Azacitidine; Carcinogenesis; Carcinoma, Hepatocellular; Cell Line, Tumor; DNA Methylation; Down-Regulation; Enzyme Inhibitors; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Homozygote; Humans; Hydroxamic Acids; Liver Neoplasms; Microarray Analysis; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Receptor-Like Protein Tyrosine Phosphatases, Class 2; Sequence Deletion

Ovarian cancer is one of the most lethal female malignancies and epigenetic abnormalities are thought to play a vital role in the pathogenesis, development and progression of ovarian cancer. Our goal was to investigate whether the combination of trichostatin A (TSA) and 5-aza-2'-deoxycytidine (decitabine) was superior to single agent on tumorigenicity of ovarian cancer cells. We found that tumorigenicity and metastasis of SKOV3 cells were significantly suppressed by the combination of TSA and decitabine in xenograft mouse models. Migration capacity was markedly suppressed through the induction of E-cadherin and suppression of N-cadherin when treated with TSA and decitabine. Invasion was also suppressed at least partially through inhibition of MMP-2 and MMP-9 with the combined treatment. The combination drugs markedly inhibited spheroid formation and significantly impaired migration and invasion capacity of spheroid derived cells through inhibition of Twist, N-cadherin, MMP-2, MMP-9 and induction of E-cadherin. Epigenetically, the activity of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) were markedly inhibited when TSA was used in combination with decitabine, especially the expression of DNMT3A/3B and HDAC1/2. Acetylation of histone H3 and H4 were more markedly stimulated with the combination than with either agent alone. The expression level of lysine-specific demethylase-1 (LSD1) was also suppressed. The transcription activity marker dimethylated-H3K4 was induced, but the dimethylated-H3K9 was suppressed by exposure to the combined drugs. These results suggest that the combination of TSA and decitabine significantly suppresses tumorigenicity by inhibiting migration and invasion of ovarian cancer cells via regulating the expression of the cadherins and MMPs, which may be epigenetically regulated by DNA methylation and histone modification.

Topics: Acetylation; Animals; Ascites; Azacitidine; Cadherins; Carcinogenesis; Cell Movement; Decitabine; DNA Methylation; DNA Modification Methylases; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Histone Demethylases; Histones; Humans; Hydroxamic Acids; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Mice; Mice, Inbred C3H; Mice, SCID; Neoplasm Invasiveness; Neoplasm Metastasis; Nuclear Proteins; Ovarian Neoplasms; Spheroids, Cellular; Tumor Cells, Cultured; Twist-Related Protein 1

RhoB, a member of small GTPases belonging to the Ras protein superfamily, might have a suppressive activity in cancer progression. Here, expression of RhoB gene was evaluated in human benign, borderline and malignant ovary tumors by immunostaining, with normal ovary tissue as control. Malignant tumors were assessed according to Federation Internationale de Gynecologie Obstetrique (FIGO) guidelines and classified in stage I-IV. Revivification of RhoB gene was investigated by analyzing the effect of histone deacetylase (HDAC) inhibitor trichostatin (TSA) and methyltransferase inhibitor 5-azacytidine (5-Aza) on ovarian cancer cells via RT-PCR and western blot. Apoptosis of ovary cancer cells was detected using flowcytometry and fluorescence microscopy. Subsequently, RhoB expression is detected in normal ovary epithelium, borderline tumors, and decreases significantly or lost in the majority of ovarian cancer specimen (P<0.05). RhoB expression decreases significantly from stage II (71.4%) to stage III (43.5%) to stage IV (18.2%, P<0.05). TSA can both significantly revive the RhoB gene and mediate apoptosis of ovarian cancer cells, but 5-Aza couldn't. Interference into Revivification of RhoB gene results in reduction of ovary carcinoma cell apoptosis. It is proposed that loss of RhoB expression occurs frequently in ovary carcinogenesis and progression and its expression could be regulated by histone deacetylation but not by promoter hypermethylation, which may serve as a prospective gene treatment target for the patients with ovarian malignancy not responding to standard therapies.

Topics: Antineoplastic Agents; Azacitidine; Carcinogenesis; Case-Control Studies; Cystadenoma, Serous; DNA Methylation; DNA, Neoplasm; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Histone Deacetylases; Humans; Hydroxamic Acids; Methyltransferases; Neoplasm Staging; Ovarian Neoplasms; Ovary; rhoB GTP-Binding Protein