MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells

Altman, Brian J.; Hsieh, Annie L.; Sengupta, Arjun; Krishnanaiah, Saikumari Y.; Stine, Zachary E.; Walton, Zandra E.; Gouw, Arvin M.; Venkataraman, Anand; Li, Bo; Goraksha-Hicks, Pankuri; Diskin, Sharon J.; Bellovin, David I.; Simon, M. Celeste; Rathmell, Jeffrey C.; Lazar, Mitchell A.; Maris, John M.; Felsher, Dean W.; Hogenesch, John B.; Weljie, Aalim M.; Dang, Chi V.

doi:10.1016/j.cmet.2015.09.003

Cited by 243 publications

(310 citation statements)

References 48 publications

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“…Since ubiquitylation and proteasome activity have been shown to regulate CLOCK and BMAL1 activation of target genes (Luo et al; Stratmann et al, 2012; Tamayo et al, 2015), the novel function of CRY proteins described here may play a role in circadian clock function. Intriguingly, c-MYC can interfere with CLOCK and BMAL1-dependent transactivation (Altman et al, 2015), so CRY2-driven MYC destabilization could reinforce circadian clock amplitude.…”

Section: Discussionmentioning

confidence: 99%

CRY2 and FBXL3 Cooperatively Degrade c-MYC

et al. 2016

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SUMMARY For many years, a connection between circadian clocks and cancer has been postulated. Here, we describe an unexpected function for the circadian repressor CRY2 as a component of an FBXL3-containing E3 ligase that recruits T58-phosphorylated c-MYC for ubiquitylation. c-MYC is a critical regulator of cell proliferation; T58 is central in a phosphodegron long recognized as a hotspot for mutation in cancer. This site is also targeted by FBXW7, though the full machinery responsible for its turnover has remained obscure. CRY1 cannot substitute for CRY2 in promoting c-MYC degradation; their unique functions may explain prior conflicting reports that have fueled uncertainty about the relationship between clocks and cancer. Thus, we demonstrate that c-MYC is a target of CRY2-dependent protein turnover, suggesting a molecular mechanism for circadian control of cell growth and a new paradigm for circadian protein degradation.

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Section: Discussionmentioning

confidence: 99%

CRY2 and FBXL3 Cooperatively Degrade c-MYC

et al. 2016

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“…Over-expression of c-MYC occurs in a wide variety of cancers including gliomas. c-MYC is a multi-functional transcription factor and the list of its target genes include those involved in both cell proliferation and cell metabolism (Miller et al, 2012; Zwaans and Lombard, 2014; Altman et al, 2015; Hsieh et al, 2015; Stine et al, 2015). In addition to stimulating glycolysis, c-MYC has been found to activate glutaminolysis and lipid synthesis from citrate (Obre and Rossignol, 2015).…”

Section: Tumor Metabolismmentioning

confidence: 99%

Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

Woolf

Syed

Scheck

2016

Front. Mol. Neurosci.

103

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Malignant brain tumors are devastating despite aggressive treatments such as surgical resection, chemotherapy and radiation therapy. The average life expectancy of patients with newly diagnosed glioblastoma is approximately ~18 months. It is clear that increased survival of brain tumor patients requires the design of new therapeutic modalities, especially those that enhance currently available treatments and/or limit tumor growth. One novel therapeutic arena is the metabolic dysregulation that results in an increased need for glucose in tumor cells. This phenomenon suggests that a reduction in tumor growth could be achieved by decreasing glucose availability, which can be accomplished through pharmacological means or through the use of a high-fat, low-carbohydrate ketogenic diet (KD). The KD, as the name implies, also provides increased blood ketones to support the energy needs of normal tissues. Preclinical work from a number of laboratories has shown that the KD does indeed reduce tumor growth in vivo. In addition, the KD has been shown to reduce angiogenesis, inflammation, peri-tumoral edema, migration and invasion. Furthermore, this diet can enhance the activity of radiation and chemotherapy in a mouse model of glioma, thus increasing survival. Additional studies in vitro have indicated that increasing ketones such as β-hydroxybutyrate (βHB) in the absence of glucose reduction can also inhibit cell growth and potentiate the effects of chemotherapy and radiation. Thus, while we are only beginning to understand the pluripotent mechanisms through which the KD affects tumor growth and response to conventional therapies, the emerging data provide strong support for the use of a KD in the treatment of malignant gliomas. This has led to a limited number of clinical trials investigating the use of a KD in patients with primary and recurrent glioma.

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“…Using tumor temperature as a marker rhythm, chronoradiotherapy for patients with cancers of the oral cavity led to a faster tumor regression rate and doubling of 2-year disease-free survival rates when it was applied at the time of peak tumor temperature, as compared to 4 or 8 h before or after that time or without consideration of circadian timing (treatment as usual) [46] . Circadian genes have now been linked to tumor suppression and disruptions in circadian genes related to cancer growth [47] , the amplitude of circadian rhythms being associated with the prognosis of cancer patients.…”

Section: Cornelissen/otsukamentioning

confidence: 99%

Chronobiology of Aging: A Mini-Review

Cornélissen

Otsuka

2016

Gerontology

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Aging is generally associated with weakening of the circadian system. The circadian amplitude is reduced and the circadian acrophase becomes more labile, tending to occur earlier with advancing age. As originally noted by Franz Halberg, similar features are observed in the experimental laboratory after bilateral lesioning of the suprachiasmatic nuclei, suggesting the involvement of clock genes in the aging process as they are in various disease conditions. Recent work has been shedding light on underlying pathways involved in the aging process, with the promise of interventions to extend healthy life spans. Caloric restriction, which is consistently and reproducibly associated with prolonging life in different animal models, is associated with an increased circadian amplitude. These results indicate the critical importance of chronobiology in dealing with problems of aging, from the circadian clock machinery orchestrating metabolism to the development of geroprotectors. The quantitative estimation of circadian rhythm characteristics interpreted in the light of time-specified reference values helps (1) to distinguish effects of natural healthy aging from those associated with disease and predisease; (2) to detect alterations in rhythm characteristics as markers of increased risk before there is overt disease; and (3) to individually optimize by timing prophylactic and/or therapeutic interventions aimed at restoring a disturbed circadian system and/or enhancing a healthy life span. Mapping changes in amplitude and/or acrophase that may overshadow any change in average value also avoids drawing spurious conclusions resulting from data collected at a fixed clock hour. Timely risk detection combined with treatment optimization by timing (chronotherapy) is the goal of several ongoing comprehensive community-based studies focusing on the well-being of the elderly, so that longevity is not achieved at the cost of a reduced quality of life.

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MYC Disrupts the Circadian Clock and Metabolism in Cancer Cells

Cited by 243 publications

References 48 publications

CRY2 and FBXL3 Cooperatively Degrade c-MYC

CRY2 and FBXL3 Cooperatively Degrade c-MYC

Tumor Metabolism, the Ketogenic Diet and β-Hydroxybutyrate: Novel Approaches to Adjuvant Brain Tumor Therapy

Chronobiology of Aging: A Mini-Review

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