Epigenetic Inactivation of the Circadian Clock Gene <i>BMAL1</i> in Hematologic Malignancies

Taniguchi, Hiroaki; Fernández, Agustín F.; Setién, Fernando; Ropero, Santiago; Ballestar, Esteban; Villanueva, Alberto; Yamamoto, Hiroyuki; Imai, Kohzoh; Shinomura, Yasuhisa; Esteller, Manel

doi:10.1158/0008-5472.can-09-0551

Cited by 162 publications

(127 citation statements)

References 30 publications

(41 reference statements)

Supporting

Mentioning

119

Contrasting

Unclassified

Order By: Relevance

“…Bmal1 was suggested to be a positive regulator of tumor growth and metastasis, acting by expressing vascular endothelial growth factor in cancer (27). Bmal1 epigenetic inactivation contributes to the development of hematologic malignancies by disrupting the cellular circadian clock (28). per1 inactivation is thought to play an important role in carcinogenesis (29).…”

Section: Discussionmentioning

confidence: 99%

Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer

Oshima

2011

Oncol Rep

100

View full text Add to dashboard Cite

Abstract. circadian rhythms are daily oscillations in various biological processes, generated by the feedback loops of eight core circadian genes: Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Clock, Bmal1 and Casein Kinase I ε (CKIε). recent studies have suggested that circadian genes participate in the growth and development of various cancers. this study examined the relations of circadian gene expression to clinicopathological factors and outcomes in patients with colorectal cancer. We studied surgical specimens of cancer tissue and adjacent normal mucosa obtained from 202 patients with untreated colorectal cancer. the relative expression levels of the circadian genes in the specimens were measured by quantitative real-time, reverse-transcription polymerase chain reaction. expression of the Clock gene and the CKIε gene in cancer tissue were significantly higher compared to that in adjacent normal mucosa. expression of the Per1 and Per3 genes in cancer tissue was significantly lower compared to that in adjacent normal mucosa. Analysis of the relations between clinicopathological features and expression of the eight circadian genes in cancer tissue showed that high expression of the Bmal1 gene and low expression of the Per1 gene correlated with liver metastasis. on analysis of the relations between outcomes and gene expression, high expression of the Per2 gene was associated with significantly better outcomes than low expression of the Per2 gene. overexpression of the Bmal1 gene and reduced expression of the Per1 gene may thus be useful predictors of liver metastasis. Moreover, reduced expression of the Per2 gene may be a predictor of outcomes in patients with colorectal cancer. Introductioncircadian rhythms are daily oscillations in various biologic processes. In mammals, the master circadian pacemaker is located in the suprachiasmatic nuclei (scn) (1). the master circadian clock coordinates peripheral circadian clocks within virtually every cell in the body (2). this coordination is accomplished directly through autonomic nervous system innervation and indirectly through daily rhythmic synthesis and release of an array of hypothalamic, pituitary, and dispersed endocrine hormones (3-6). the molecular mechanism of circadian oscillation in the scn and peripheral cells is based on the feedback loops of eight core circadian genes (3,7,8). these eight genes are Period1 (Per1), Period2 (Per2), Period3 (Per3), Cryptochrome1 (Cry1), Cryptochrome2 (Cry2), Clock, Bmal1, and Casein Kinase I ε (CKIε). the feedback loops of the eight core circadian genes are as follows. the Clock gene remains steady throughout the 24-h day. High levels of Bmal1 promote the formation of Bmal1/clock heterodimers. these heterodimers bind to e-box sequences in the promoters of the Cry and Per genes to activate transcription. Bmal1/clock heterodimers can also inhibit Bmal1 transcription. After transcription and translation, the per proteins accumulate in the cytoplasm and are phosphorylated by...

show abstract

Section: Discussionmentioning

confidence: 99%

Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer

Oshima

2011

Oncol Rep

100

View full text Add to dashboard Cite

show abstract

“…Parkinson (Lin et al, 2012), whereas DNA hypermethylation-associated loss of BMAL1, which has been reported in leukemia/lymphoma cells, prevents the recruitment of its natural partner, CLOCK, to their common targets, further enhancing the perturbed circadian rhythm of the cancer cells (Taniguchi et al, 2009). Very importantly, a maternal diet rich in fat modulates in utero the acetylation of fetal histone H3 at lysine 14 (H3K14ac) in NPAS2, a paralog of the CLOCK transcription factor, affecting thus the peripheral circadian system of the fetus .…”

Section: Circadian Rhythms and Sleepmentioning

confidence: 96%

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Milagro

Mansego

Miguel

et al. 2013

Molecular Aspects of Medicine

247

161

View full text Add to dashboard Cite

Nutritional factors play a life-long role in human health. Indeed, there is growing evidence that one of the mechanisms by which nutrients and bioactive compounds affect metabolic traits is epigenetics. Complex interactions among food components and histone modifications, DNA methylation, non-coding RNA expression and chromatin remodeling factors lead to a dynamic regulation of gene expression that controls the cellular phenotype. Although perinatal period is the time of highest phenotypic plasticity, contributing largely to developmental programming, also during adulthood there is evidence about a nutritional influence on epigenetic regulation. Similarly to type 2 diabetes, hypertension, atherosclerosis and other metabolic disorders, obesity predisposition and weight loss outcomes have been repeatedly associated to changes in epigenetic patterns. Different non-nutritional risk factors that usually accompany obesity seem also to be involved in these epigenetic modifications, especially hyperglycemia, inflammation, hypoxia and oxidative stress. There are currently three major objectives in epigenetic research in relation to obesity: to search for epigenetic biomarkers to predict future health problems or detect the individuals at most risk, to understand the obesity-related environmental factors that could modulate gene expression by affecting epigenetic mechanisms, and to study novel therapeutic strategies based on nutritional or pharmacological agents that can modify epigenetic marks. At this level, the major tasks are: development of robust epigenetic biomarkers of weight regulation, description of those epigenetic marks more susceptible to be modified by dietary exposures, identification of the active ingredients (and the doses) that alter the epigenome, assessment of the real importance of other obesity-related factors on epigenetic regulation, determination of the period of life in which best results are obtained, and understanding of the importance of the inheritance of these epigenetic marks.

show abstract

“…Deregulated expression of the PER1, PER2 and PER3 genes as well as inactivation or knockout PER1, PER2, CLOCK and BMAL1 leads to malignization, especially in the breast, as well as to the appearance of different disorders such as obesity [22][23][24][25]. In the regulation of circadian clock system casein kinases play an important role, especially casein kinase-1ε (CSNK1E) and -1δ (CSNK1D) [26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Expression of casein kinase genes in glioma cell line U87: Effect of hypoxia and glucose or glutamine deprivation

Minchenko¹,

Karbovskyi²,

Danilovskyi³

et al. 2012

View full text Add to dashboard Cite

The endoplasmic reticulum-nuclei-1 (ERN1) sensing and signaling enzyme mediates a set of complex intracellular signaling events known as the unfolded protein response. We have studied the effect of hypoxia and ischemic conditions (glucose or glutamine deprivation) on the expression of several casein kinase-1 and -2 genes in glioma U87 cells and its subline with suppressed function of ERN1. It was shown that blockade of ERN1, the key endoplasmic reticulum stress sensor, leads to an increase in the expression levels of casein kinase-1G2, -1E, -2B and NUCKS1 mRNA, but suppresses casein kinase-1A1, -1D and -2A1. Moreover, the expression levels of casein kinase-1A1, -1D and 1G3 as well as casein kinase-2A1 and -2A2 mRNAs are significantly increased under glutamine deprivation conditions both in control and ERN1-deficient glioma cells. At the same time, casein kinase-1E, -2B and NUCKS1 mRNA expression levels are also increased under this condition, but only in cells with suppressed function of ERN1. The expression level of NUCKS1 mRNA, however, is decreased both in control glioma cells and in genetically modified cells, but casein kinase-1G2-only in control U87 cells. Cell exposure to glucose deprivation conditions enhances the expression levels of casein kinase-1D, 1G3, -1E and -2A1 in both types of glioma cells used, but casein kinase-2B expression levels increase only in cells with suppressed function of ERN1. Hypoxia induces or suppresses the expression of most of the studied genes mainly in ERN1-knockdown cells only. Results of this study show that hypoxia as well as glutamine and glucose deprivation conditions change the expression level most of casein kinase genes and that these effects are dependent on ERN1 signaling enzyme function.

show abstract

Epigenetic Inactivation of the Circadian Clock Gene BMAL1 in Hematologic Malignancies

Cited by 162 publications

References 30 publications

Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer

Expression of circadian genes correlates with liver metastasis and outcomes in colorectal cancer

Dietary factors, epigenetic modifications and obesity outcomes: Progresses and perspectives

Expression of casein kinase genes in glioma cell line U87: Effect of hypoxia and glucose or glutamine deprivation

Contact Info

Product

Resources

About