Circadian Clock, Cancer, and Chemotherapy

Sancar, Aziz; Lindsey-Boltz, Laura A.; Gaddameedhi, Shobhan; Selby, Christopher P.; Rui, Yong; Chiou, Yi Ying; Kemp, Michael G.; Hu, Jinchuan; Lee, Jin Hyup; Öztürk, Nuri

doi:10.1021/bi5007354

Cited by 132 publications

(138 citation statements)

References 111 publications

(306 reference statements)

Supporting

Mentioning

131

Contrasting

Order By: Relevance

“…5). Whereas the above findings are consistent with a role for PER2 in suppressing a cancer-prone phenotype, a note of caution is in order, as inconsistencies among in vitro and in vivo studies have been recently reported (6,7).…”

supporting

confidence: 60%

Model-driven experimental approach reveals the complex regulatory distribution of p53 by the circadian factor Period 2

Gotoh

Kim

Liu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The circadian clock and cell cycle networks are interlocked on the molecular level, with the core clock loop exerting a multilevel regulatory role over cell cycle components. This is particularly relevant to the circadian factor Period 2 (Per2), which modulates the stability of the tumor suppressor p53 in unstressed cells and transcriptional activity in response to genotoxic stress. Per2 binding prevents Mdm2-mediated ubiquitination of p53 and, therefore, its degradation, and oscillations in the peaks of Per2 and p53 were expected to correspond. However, our findings showed that Per2 and p53 rhythms were significantly out-of-phase relative to each other in cell lysates and in purified cytoplasmic fractions. These seemingly conflicting experimental data motivated the use of a combined theoretical and experimental approach focusing on the role played by Per2 in dictating the phase of p53 oscillations. Systematic modeling of all possible regulatory scenarios predicted that the observed phase relationship between Per2 and p53 could be simulated if (i) p53 was more stable in the nucleus than in the cytoplasm, (ii) Per2 associates to various ubiquitinated forms of p53, and (iii) Per2 mediated p53 nuclear import. These predictions were supported by a sevenfold increase in p53's half-life in the nucleus and by in vitro binding of Per2 to the various ubiquitinated forms of p53. Last, p53's nuclear shuttling was significantly favored by ectopic expression of Per2 and reduced because of Per2 down-regulation. Our combined theoretical/mathematical approach reveals how clock regulatory nodes can be inferred from oscillating time course data. tumor suppressor | circadian rhythms | p53 | mathematical modeling | Period 2

show abstract

supporting

confidence: 60%

Model-driven experimental approach reveals the complex regulatory distribution of p53 by the circadian factor Period 2

Gotoh

Kim

Liu

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…DEC1 is a well-known controller of mammalian molecular clock (5). Recently, the chronochemotherapy based on the clock genes attracted more and more attention (14). Rhythm analysis of DEC1 under hypoxic condition could be taken into consideration in our future study.…”

Section: Hif-1α Knockdown Failed To Alter the Expression Of Dec1mentioning

confidence: 99%

<b>DEC1 promotes hypoxia-induced epithelial-mesenchymal transition (EMT) in human hepatocellular carcinoma </b><b>cells </b>

Murakami

Imaizumi

et al. 2017

Biomed. Res.

View full text Add to dashboard Cite

Differentiated embryonic chondrocyte (DEC) 1 has been reported to be involved in cell differentiation, hypoxia response, and cancer progression. Recent studies have demonstrated that hypoxiainducible factor (HIF)-1α induces epithelial-mesenchymal transition (EMT) in carcinoma cells to facilitate cell invasiveness and metastasis. However, it remains unclear whether DEC1 participates in hypoxia-mediated EMT processes. In the present study, we reported that hypoxia induced DEC1 expression in hepatocellular carcinoma (HCC) HepG2 cells, and DEC1 negatively regulated expression of HIF-1α and E-cadherin in transcriptional/translational levels. Cell morphological changes were evaluated with hematoxylin and eosin (H-E) staining. Exposure to hypoxia caused spindle-like shape in some of the HepG2 cells, and DEC1 overexpression furthered these changes. In conclusions, DEC1 is involved in hypoxia-induced EMT processes via negatively regulating E-cadherin expression in HepG2 cells.There has been a great discussion about the relation between hypoxia and epithelial-mesenchymal transition (EMT). Intratumoral hypoxia followed by stabilization of hypoxia-inducible factor (HIF)-1α promotes acquisition of EMT-like features in various kinds of carcinomas (2, 9, 11, 18) as well as hematopoietic tumors (1). Several studies have reported that HIF-1α overexpression is positively correlated with EMT induction in hepatocellular carcinoma (HCC) cell lines and surgical resection specimens (7,8,20). In addition, hypoxia-induced EMT resulted in multidrug resistance in HCC cells (16), tumor metastasis after transcatheter arterial embolization (TAE) (4), and poor prognosis in HCC patients (6). It has been shown that curcumin, a botanical agent derived from the dried rhizome of Curcuma longa, eliminates the accumulation of HIF-1α to reduce the invasive potential of HepG2 cells (3). These findings indicated that hypoxia-induced EMT may be a significant prognosis marker and a crucial therapy target of HCC patients. Differentiated embryonic chondrocyte expressed gene (DEC) 1 (BHLHE40/Stra13/Sharp2) has been found as a transcriptional factor promoting the differentiation of chondrocytes (15) and regulating the circadian rhythm via suppressing CLOCK/BMAL1-enhanced promoter activity (5). Recently, DEC1 has been reported to be located on the downstream of HIF-1α pathway and the activation of HIF-1α and DEC1 causes tumor progression, invasion, and metastasis (13). Our previous studies have shown that DEC1 promotes TGF-β-induced EMT of pancreatic adenocarcinoma PANC-1 cells through Smad3 phosphorylation (17). However, the relation between DEC1 and hypoxia-induced EMT has not been reported in any human cancer cell lines. This study was undertaken to examine the relation between DEC1 and hypoxia-induced EMT in human HCC HepG2 cells.

show abstract

“…To test this idea, we analyzed changes in expression profiles of cell-cycle regulators and pro-apoptotic genes that are influenced by circadian rhythm, including p53, c-myc, Cyclin D1, Wee1, BAX, and Bcl-2 [23,30,32].…”

Section: Ks15 Modulates Expression Profiles Of Circadian Clock Genes mentioning

confidence: 99%

A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells

Chun

Chung

Kim

et al. 2015

Biochemical and Biophysical Research Communications

View full text Add to dashboard Cite

Circadian Clock, Cancer, and Chemotherapy

Cited by 132 publications

References 111 publications

Model-driven experimental approach reveals the complex regulatory distribution of p53 by the circadian factor Period 2

Model-driven experimental approach reveals the complex regulatory distribution of p53 by the circadian factor Period 2

<b>DEC1 promotes hypoxia-induced epithelial-mesenchymal transition (EMT) in human hepatocellular carcinoma </b><b>cells </b>

A synthetic cryptochrome inhibitor induces anti-proliferative effects and increases chemosensitivity in human breast cancer cells

Contact Info

Product

Resources

About