Aberrant Transforming Growth Factor β1 Signaling and SMAD4 Nuclear Translocation Confer Epigenetic Repression of ADAM19 in Ovarian Cancer

Chan, Michael W.Y.; Huang, Yi‐Wen; Hartman-Frey, Corinna; Kuo, Ching‐Hua; Deatherage, Daniel E.; Qin, Huaxia; Cheng, Alfred S.L.; Yan, Pearlly S.; Davuluri, Ramana V.; Huang, Tim H.M.; Nephew, Kenneth P.; Lin, Huey‐Jen

doi:10.1593/neo.08540

Cited by 61 publications

(50 citation statements)

References 55 publications

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“…Yet, the degree of methylation in these ovarian cancer lines has not been proportionally correlated to their susceptibility to ADC (compare Fig. 3A and B), which strongly supports the notion that multiple epigenomic events beside DNA methylation can orchestrate gene expression in a cooperative manner, in consistent with we reported previously (35).…”

Section: Discussionsupporting

confidence: 91%

Identification of candidate epigenetic biomarkers for ovarian cancer detection

et al. 2009

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Abstract. Ovarian cancer ranks the most lethal among gynecologic neoplasms in women. To develop potential biomarkers for diagnosis, we have identified five novel genes (CYP39A1, GTF2A1, FOXD4L4, EBP, and HAAO) that are hypermethylated in ovarian tumors, compared with the non-malignant normal ovarian surface epithelia, using the quantitative methylation-specific polymerase chain reactions. Interestingly enough, multivariate Cox regression analysis has identified hypermethylation of CYP39A1 correlated with an increase rate of relapsing (P=0.032, hazard ratio >1).Concordant hypermethylation in at least three loci was observed in 50 out of 55 (91%) of ovarian tumors examined. The test sensitivity and specificity were assessed to be 96 and 67% for CYP39A1; 95 and 88% for GTF2A1; 93 and 67% for FOXD4L4; 81 and 67% for EBP; 89 and 82% for HAAO, respectively. Our data have identified, for the first time, GTF2A1 alone, or GTF2A1 plus HAAO are excellent candidate biomarkers for detecting this disease. Moreover, the known functions of these gene products further implicate dysregulated transcriptional control, cholesterol metabolism, or synthesis of quinolinic acids, may play important roles in attributing to ovarian neoplasm. Molecular therapies, by reversing the aberrant epigenomes using inhibitory agents or by abrogating the upstream signaling pathways that convey the epigenomic perturbations, may be developed into promising treatment regimens. IntroductionOvarian cancer remains the most lethal malignancy of the female reproductive tract, and is ranked as the fourth leading cause of cancer death in women (1). While there are over 20,000 new cases diagnosed annually, approximately 15,000 deaths are reported in the United States each year (1). Typically, ovarian cancer is asymptomatic in the early stages and hence three-fourths of women are diagnosed after the disease has metastasized beyond the primary site which frequently causes poor prognostic outcomes. Investigation of early molecular events resulting in ovarian cancer has been hampered by the lack of identifiable precursor lesions as well as poor biomarkers for laboratorial tests. Currently, the only clinically accepted biomarker is CA125, which is found elevated in the serum of the majority of ovarian cancers (reviewed in ref.2). Although CA125 has high clinical sensitivity, its use for early ONCOLOGY REPORTS 22: 853-861, 2009 Abbreviations: DAC, 5-aza-2'-deoxycytidine; nOSE, normal ovarian surface epithelia; qMSP, quantitative methylation-specific polymerase chain reactions; qRT-PCR, quantitative reverse transcription followed by polymerase chain reactions; TSA, trichostatin A

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Section: Discussionsupporting

confidence: 91%

Identification of candidate epigenetic biomarkers for ovarian cancer detection

et al. 2009

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“…These modifications include acetylation, methylation, and phosphorylation. Genes involved in cell cycle regulation, such as cyclinB1 (Valls et al, 2005), p21 (Richon et al, 2000), and ADAM19 (Chan et al, 2008) have been indicated to be regulated by histone modification. Overexpression of the cancer-promoting genes claudin-3 and claudin-4 in ovarian cancer is associated with loss of trimethylated histone 3 lysine 27 (H3K27me3) (Kwon et al, 2010).…”

Section: Epigenomic Mechanisms On the Development Of Ovarian Cancermentioning

confidence: 99%

Epigenomics of Ovarian Cancer and Its Chemoprevention

Chen¹,

Hardy²,

Tollefsbol³

2011

Front. Gene.

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Ovarian cancer is a major cause of death among gynecological cancers and its etiology is still unclear. Currently, the two principle obstacles in treating this life threatening disease are lack of effective biomarkers for early detection and drug resistance after initial chemotherapy. Similar to other cancers, the initiation and development of ovarian cancer is characterized by disruption of oncogenes and tumor suppressor genes by both genetic and epigenetic mechanisms. While it is well known that it is challenging to treat ovarian cancer through a genetic strategy due in part to its heterogeneity, the reversibility of epigenetic mechanisms involved in ovarian cancer opens exciting new avenues for treatment. The epigenomics of ovarian cancer has therefore become a rapidly expanding field leading to intense investigation. A review on the current status of the field is thus warranted. In this analysis, we will evaluate the current status of epigenomics of ovarian cancer and will include epigenetic mechanisms involved in ovarian cancer development such as DNA methylation, histone modifications, and non-coding microRNA. Development of biomarkers, the epigenetic basis for drug resistance and improved chemotherapy for ovarian cancer will also be assessed. In addition, the potential use of natural compounds as epigenetic modulators in chemotherapy shows promise in moving to the forefront of ovarian cancer treatment strategies.

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“…Our previous study revealed that downregulation of TGFβ target genes are observed in a panel of ovarian cancer cell lines. 14,18 To examine if a similar phenomenon can be observed for RunX1T1, mRNA levels of RunX1T1 were examined by quantitative real time RT-PCR in the same panel of cancer cell lines (namely, HeyC2, SKOV3, MCP3, MCP2, A2780 and CP70). Lower or no expression of RunX1T1 expression was found in all ovarian cancer cell lines as compared with IOSE cells ( Fig.…”

Section: Resultsmentioning

confidence: 96%

Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor,RunX1T1in ovarian cancer

et al. 2011

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Aberrant TGFβ signaling pathway may alter the expression of down-stream targets and promotes ovarian carcinogenesis. However, the mechanism of this impairment is not fully understood. Our previous study has identified RunX1T1 as a putative SMAD4 target in an immortalized ovarian surface epithelial cell line, IOSE. In this study, we report that transcription of RunX1T1 was confirmed to be positively regulated by SMAD4 in IOSE cells and epigenetically silenced in a panel of ovarian cancer cell lines by promoter hypermethylation and histone methylation at H3 lysine 9. SMAD4 depletion increased repressive histone modifications of RunX1T1 promoter without affecting promoter methylation in IOSE cells. Epigenetic treatment can restore RunX1T1 expression by reversing its epigenetic status in MCP3 ovarian cancer cells. When transiently treated with a demethylating agent, the expression of RunX1T1 was partially restored in MCP3 cells, but gradual re-silencing through promoter re-methylation was observed after the treatment. Interestingly, SMAD4 knockdown accelerated this re-silencing process, suggesting that normal TGF-beta signaling is essential for the maintenance of RunX1T1 expression. In vivo analysis confirmed that hypermethylation of RunX1T1 was detected in 35.7% (34/95) of ovarian tumors with high clinical stages (P=0.035) and in 83% (5/6) of primary ovarian cancer-initiating cells. Additionally, concurrent methylation of RunX1T1 and another SMAD4 target, FBXO32 which was previously found to be hypermethylated in ovarian cancer was observed in this same sample cohort (P< 0.05). Restoration of RunX1T1 inhibited cancer cell growth. Taken together, dysregulated TGFβ/SMAD4 signaling may lead to epigenetic silencing of a putative tumor suppressor, RunX1T1, during ovarian carcinogenesis.

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Aberrant Transforming Growth Factor β1 Signaling and SMAD4 Nuclear Translocation Confer Epigenetic Repression of ADAM19 in Ovarian Cancer

Cited by 61 publications

References 55 publications

Identification of candidate epigenetic biomarkers for ovarian cancer detection

Identification of candidate epigenetic biomarkers for ovarian cancer detection

Epigenomics of Ovarian Cancer and Its Chemoprevention

Aberrant TGFβ/SMAD4 signaling contributes to epigenetic silencing of a putative tumor suppressor,RunX1T1in ovarian cancer

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