Targeting Calcium Signaling Induces Epigenetic Reactivation of Tumor Suppressor Genes in Cancer.
Cancer Research 76(6):1494 (2016)
Targeting epigenetic pathways is a promising approach for cancer therapy. Here, we report on the unexpected finding that targeting calcium signaling can reverse epigenetic silencing of tumor suppressor genes (TSG). In a screen for drugs that reactivate silenced gene expression in colon cancer ce...
Differentially methylated genes and androgen receptor re-expression in small cell prostate carcinomas.
Epigenetics 11(3):184 (2016)
Small cell prostate carcinoma (SCPC) morphology is rare at initial diagnosis but often emerges during prostate cancer progression and portends a dismal prognosis. It does not express androgen receptor (AR) or respond to hormonal therapies. Clinically applicable markers for its early detection an...
Hypomethylation of TET2 Target Genes Identifies a Curable Subset of Acute Myeloid Leukemia.
JNCI Journal of the National Cancer Institute 108(2) (2016)
Acute myeloid leukemia (AML) is curable in a subset of cases. The DNA methylation regulator TET2 is frequently mutated in AML, and we hypothesized that studying TET2-specific differentially methylated CpGs (tet2-DMCs) improves AML classification.
We used bisulfite pyrosequencing to analyze the m...
Zebrafish embryos as a screen for DNA methylation modifications after compound exposure.
Toxicology and Applied Pharmacology 291:84 (2016)
Modified epigenetic programming early in life is proposed to underlie the development of an adverse adult phenotype, known as the Developmental Origins of Health and Disease (DOHaD) concept. Several environmental contaminants have been implicated as modifying factors of the developing epigenome....
G9a is essential for epigenetic silencing of K(+) channel genes in acute-to-chronic pain transition.
Nature Neuroscience 18(12):1746 (2015)
Neuropathic pain is a debilitating clinical problem and difficult to treat. Nerve injury causes a long-lasting reduction in K(+) channel expression in the dorsal root ganglion (DRG), but little is known about the epigenetic mechanisms involved. We found that nerve injury increased dimethylation ...
New DNA methylation markers and global DNA hypomethylation are associated with oral cancer development.
Cancer Prevention Research 8(11):1027 (2015)
DNA promoter methylation of tumor suppressor genes and global DNA hypomethylation are common features of head and neck cancers. Our goal was to identify early DNA methylation changes in oral premalignant lesions (OPL) that may serve as predictive markers of developing oral squamous cell carcinom...
TET2 Mutations Affect Non-CpG Island DNA Methylation at Enhancers and Transcription Factor-Binding Sites in Chronic Myelomonocytic Leukemia.
Cancer Research 75(14):2833 (2015)
TET2 enzymatically converts 5-methylcytosine to 5-hydroxymethylcytosine as well as other covalently modified cytosines and its mutations are common in myeloid leukemia. However, the exact mechanism and the extent to which TET2 mutations affect DNA methylation remain in question. Here, we report ...
Epigenetic synergy between decitabine and platinum derivatives.
Clinical Epigenetics 7(1):97 (2015)
Aberrant epigenetic silencing of tumor suppressor genes has been recognized as a driving force in cancer. Epigenetic drugs such as the DNA methylation inhibitor decitabine reactivate genes and are effective in myeloid leukemia, but resistance often develops and efficacy in solid tumors is limite...
Minimal role of base excision repair in TET-induced global DNA demethylation in HEK293T cells.
Epigenetics 10(11):1006 (2015)
Oxidation of 5-methylcytosine by TET family proteins can induce DNA replication-dependent (passive) DNA demethylation and base excision repair (BER)-based (active) DNA demethylation. The balance of active vs. passive TET-induced demethylation remains incompletely determined. In the context of la...
Methylome sequencing for fibrolamellar hepatocellular carcinoma depicts distinctive features.
Epigenetics 10(9):872 (2015)
With the goal of studying epigenetic alterations in fibrolamellar hepatocellular carcinoma (FLC) and establish an associated DNA methylation signature, we analyzed LINE-1 methylation in a cohort of FLC and performed next-generation sequencing of DNA methylation in a training set of pure-FLCs and...
Phase I study of azacitidine and oxaliplatin in patients with advanced cancers that have relapsed or are refractory to any platinum therapy.
Clinical Epigenetics 7(1):29 (2015)
Demethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may res...
Decreased efficacy of drugs targeting the vascular endothelial growth factor pathway by the epigenetic silencing of FLT1 in renal cancer cells.
Clinical Epigenetics 7(1):99 (2015)
The vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling pathway is involved in cancer-related biological functions and is a therapeutic target in cancer. However, the influence of epigenetic regulation of VEGF-VEGFR signaling-related genes remains unclear. Here, we evaluate...
TET1 is a maintenance DNA demethylase that prevents methylation spreading in differentiated cells.
Nucleic Acids Research 42(11):6956 (2014)
TET1 is a 5-methylcytosine dioxygenase and its DNA demethylating activity has been implicated in pluripotency and reprogramming. However, the precise role of TET1 in DNA methylation regulation outside of developmental reprogramming is still unclear. Here, we show that overexpression of the TET1 ...
Age-related epigenetic drift in the pathogenesis of MDS and AML.
Genome Research 24(4):580 (2014)
The myelodysplastic syndrome (MDS) is a clonal hematologic disorder that frequently evolves to acute myeloid leukemia (AML). Its pathogenesis remains unclear, but mutations in epigenetic modifiers are common and the disease often responds to DNA methylation inhibitors. We analyzed DNA methylatio...
Epigenetic reprogramming of HOXC10 in endocrine-resistant breast cancer.
Science Translational Medicine 6(229):229ra41 (2014)
Resistance to aromatase inhibitors (AIs) is a major clinical problem in the treatment of estrogen receptor (ER)-positive breast cancer. In two breast cancer cell line models of AI resistance, we identified widespread DNA hyper- and hypomethylation, with enrichment for promoter hypermethylation o...
Fusobacterium in colonic flora and molecular features of colorectal carcinoma.
Cancer Research 74(5):1311 (2014)
Fusobacterium species are part of the gut microbiome in humans. Recent studies have identified overrepresentation of Fusobacterium in colorectal cancer tissues, but it is not yet clear whether this is pathogenic or simply an epiphenomenon. In this study, we evaluated the relationship between Fus...
Colorectal carcinomas with CpG island methylator phenotype 1 frequently contain mutations in chromatin regulators.
Gastroenterology 146(2):530 (2014)
Subgroups of colorectal carcinomas (CRCs) characterized by DNA methylation anomalies are termed CpG island methylator phenotype (CIMP)1, CIMP2, or CIMP-negative. The pathogenesis of CIMP1 colorectal carcinomas, and their effects on patients' prognoses and responses to treatment, differ from thos...
Impact of decitabine on immunohistochemistry expression of the putative tumor suppressor genes FHIT, WWOX, FUS1 and PTEN in clinical tumor samples.
Clinical Epigenetics 6(1):13 (2014)
Since tumor suppressor gene function may be lost through hypermethylation, we assessed whether the demethylating agent decitabine could increase tumor suppressor gene expression clinically. For fragile histidine triad (FHIT), WW domain-containing oxidoreductase (WWOX), fused in sarcoma-1 (FUS1) ...
Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.
Clinical Epigenetics 6(1):2 (2014)
In 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherap...
Examination of whole blood DNA methylation as a potential risk marker for gastric cancer.
Cancer Prevention Research 6(10):1093 (2013)
Whole blood DNA methylation analysis has been proposed to be a risk marker for cancer that can be used to target patients for preventive interventions. To test this, we examined whole blood DNA methylation of 16 CpG island promoters and LINE1 repetitive element in patients with gastric cancer an...