Promoter methylation in circadian genes of endometrial cancers detected by methylation‐specific PCR

Shih, Mu‐Chin; Yeh, Kun‐Tu; Tang, Kai-Ping; Chen, Jui‐Chang; Chang, Jan‐Gowth

doi:10.1002/mc.20198

Cited by 75 publications

(50 citation statements)

References 40 publications

(61 reference statements)

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“…When rhythms of clock genes were suppressed in jet-lagged mice, down-regulation of p53 and overexpression of c-myc occurred, and both effects also favor cancer growth (35). Down-regulation of circadian gene expression may actually occur by epigenetic mechanisms: in endometrial cancers, CpG methylation in promoter sequences of PER1, PER2, and CRY1 was detected (36).…”

Section: Discussionmentioning

confidence: 99%

Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors

Krugluger

Brandstaetter²,

Kállay³

et al. 2007

Cancer Research

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Expression of dihydropyrimidine dehydrogenase (DPD) displays a regular daily oscillation in nonmalignant cells. In colorectal cancer cells, the expression of this 5-fluorouracilmetabolizing enzyme is decreased, but the reason remains unclear. In this study, we analyzed by real-time reverse transcription-PCR (RT-PCR) the expression of DPD and of members of the cellular oscillation machinery, period 1 (Per1), period 2 (Per2), and CLOCK, in primary colorectal tumors and normal colon mucosa derived from the same patients. Analysis of tumors according to differentiation grade revealed a 0.46-fold (P = 0.005) decrease for DPD mRNA and a 0.49-fold (P = 0.004) decrease for Per1 mRNA in undifferentiated (G3) tumors compared with paired normal mucosa. In this tumor cohort, the correlation between DPD and Per1 levels was r = 0.64, P < 0.01. In moderately differentiated (G2) colon carcinomas, reduction of DPD and Per1 mRNA levels did not reach significance, but a significant correlation between the respective mRNA levels was detectable (r = 0.54; P < 0.05). The decrease and correlation of DPD and Per1 mRNA levels were even more pronounced in female (G3) patients (DPD: female, 0.35-fold, P < 0.001 versus male, 0.58-fold, P < 0.05; and Per1: female, 0.47-fold, P < 0.01 versus male, 0.52-fold, P < 0.01). The highly significant correlation of DPD mRNA with Per1 mRNA expression suggests control of DPD transcription by the endogenous cellular clock, which is more pronounced in women. Our results also revealed a disturbed transcription of Per1 during tumor progression, which might be the cause for disrupted daily oscillation of DPD in undifferentiated colon carcinoma cells. [Cancer Res 2007;67(16):7917-22]

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Section: Discussionmentioning

confidence: 99%

Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors

Krugluger

Brandstaetter²,

Kállay³

et al. 2007

Cancer Research

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“…Thus, impaired expressions of the clock genes Per1, Per2, or Per3 have been reported in human cancers originating from breast, lung, endometrium, pancreas, or colon, as well as in human myeloid leukemia Gery et al 2005Gery et al , 2006Gery et al , 2007aYeh et al 2005;Shih et al 2006;Krugluger et al 2007). Promoter methylation defects may account for such impaired clock gene expression .…”

Section: Implications For Cancer Chronotherapeuticsmentioning

confidence: 99%

Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics

Lévi

Filipski²,

Iurisci³

et al. 2007

Cold Spring Harbor Symposia on Quantitative Biology

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“…Most important, Per2-mutant mice are cancer prone, have an attenuated p53 DNA-damage response, and overexpress C-MYC (14), whereas Per2 and Per1 ectopic expression results in growth inhibition (15,16). Even more recently, preliminary reports suggest that the Period genes may undergo aberrant DNA methylation events in human tumors (17,18).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies

et al. 2009

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Disruption of circadian rhythms, daily oscillations in biological processes that are regulated by an endogenous clock, has been linked to tumorigenesis. Normal and malignant tissues often show asynchronies in cell proliferation and metabolic rhythms. Cancer chronotherapy takes biological time into account to improve the therapy. However, alterations of the circadian clock machinery genes have rarely been reported in human cancer. Herein, we show that the BMAL1 gene, a core component of the circadian clock, is transcriptionally silenced by promoter CpG island hypermethylation in hematologic malignancies, such as diffuse large B-cell lymphoma and acute lymphocytic and myeloid leukemias. We also describe how BMAL1 reintroduction in hypermethylated leukemia/lymphoma cells causes growth inhibition in colony assays and nude mice, whereas BMAL1 depletion by RNA interference in unmethylated cells enhances tumor growth. We also show that BMAL1 epigenetic inactivation impairs the characteristic circadian clock expression pattern of genes such as C-MYC, catalase, and p300 in association with a loss of BMAL1 occupancy in their respective promoters. Furthermore, the DNA hypermethylation-associated loss of BMAL1 also prevents the recruitment of its natural partner, the CLOCK protein, to their common targets, further enhancing the perturbed circadian rhythm of the malignant cells. These findings suggest that BMAL1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting the cellular circadian clock. [Cancer Res 2009;69(21):8447-54]

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Promoter methylation in circadian genes of endometrial cancers detected by methylation‐specific PCR

Cited by 75 publications

References 40 publications

Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors

Regulation of Genes of the Circadian Clock in Human Colon Cancer: Reduced Period-1 and Dihydropyrimidine Dehydrogenase Transcription Correlates in High-Grade Tumors

Cross-talks between Circadian Timing System and Cell Division Cycle Determine Cancer Biology and Therapeutics

Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies

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