Epigenetic silencing of the candidate tumor suppressor gene Per1 in non-small cell lung cancer.
ABSTRACT Epigenetic events are a critical factor contributing to cancer development. The purpose of this study was to identify tumor suppressor genes silenced by DNA methylation and histone deacetylation in non-small cell lung cancer (NSCLC).
We used microarray analysis to screen for tumor suppressor genes.
We identified Per1, a core circadian gene, as a candidate tumor suppressor in lung cancer. Although Per1 levels were high in normal lung, its expression was low in a large panel of NSCLC patient samples and cell lines. Forced expression of Per1 in NSCLC cell lines led to significant growth reduction and loss of clonogenic survival. Recent studies showed that epigenetic regulation, particularly histone H3 acetylation, is essential for circadian function. Using bisulfite sequencing and chromatin immunoprecipitation, we found that DNA hypermethylation and histone H3 acetylation are potential mechanisms for silencing Per1 expression NSCLC.
These results support the hypothesis that disruption of circadian rhythms plays an important role in lung tumorigenesis. Moreover, our findings suggest a novel link between circadian epigenetic regulation and cancer development.
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ABSTRACT: Disrupted circadian rhythms may lead to failures in the control of the cell division cycle and the subsequent malignant cell growth. In order to understand the pathogenesis of cancer more in detail, it is crucial to identify those mechanisms of action which contribute to the loss of control of the cell division cycle. This mini-review focuses on the recent findings concerning the links between the human circadian clock and cancer. Clinical implications concern not only feasible methods for the assessment of the circadian time of an individual or for the determination of the best time for administration of a drug of treatment, but also in the future genetic tests for screening and for planning treatment.Annals of medicine 10/2012; · 3.52 Impact Factor
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ABSTRACT: DNA methylation is likely to regulate the expression of clock genes during normal development and in the development of cancer. Methylation status of clock genes also appears to be associated with dementia with Lewy bodies and aging. However, there is currently no rapid, cost-effective method to examine the methylation status of clock promoters in mice. In the present study, two sets of methylation-specific polymerase chain reaction assays were developed to examine the methylation status of eight key clock genes, Bmal1, Bmal2, Clock, NPAS2, Per1, Per2, Cry1 and Cry2. Down to 1% of methylation can be examined consistently with this method, demonstrating high specificity and sensitivity. The methylation of clock promoters was examined in five peripheral tissues with the developed method; indicating that all of the clock promoters are free from methylation in the adult mouse.Biological Rhythm Research 08/2012; 43(4):341-350. · 0.47 Impact Factor
Article: Year-in-Review of Lung Cancer.[show abstract] [hide abstract]
ABSTRACT: In the last several years, we have made slow but steady progress in understanding molecular biology of lung cancer. This review is focused on advances in understanding the biology of lung cancer that have led to proof of concept studies on new therapeutic approaches. The three selected topics include genetics, epigenetics and non-coding RNA. This new information represents progress in the integration of molecular mechanisms that to identify more effective ways to target lung cancer.Tuberculosis and respiratory diseases. 09/2012; 73(3):137-42.