A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival

Bu, Yiwen; Yoshida, Akihiro; Chitnis, Nilesh; Altman, Brian J.; Tameire, Feven; Oran, Amanda; Gennaro, Victoria; Armeson, Kent; McMahon, Steven B.; Wertheim, Gerald; Dang, Chi V.; Ruggero, Davide; Koumenis, Constantinos; Fuchs, Serge Y.; Diehl, J. Alan

doi:10.1038/s41556-017-0006-y

Cited by 93 publications

(81 citation statements)

References 43 publications

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“…61 Different studies have shown that the UPR is regulated by the circadian clock. 62,63 In Burkitt's lymphoma, repression of BMAL1 is essential for the UPR-dependent inhibition of protein synthesis, 35 and it has been reported that low PER1 expression and high UPR response associate with poorer prognoses in glioblastoma patients. 64 In the current study, melatonin was able to downregulate the overexpressed chaperones HSP70, HSP90, and GRP78 from 20 weeks of DEN administration, and BMAL1 and CLOCK, the central regulator of the circadian clock, decreased from 10 weeks.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine‐induced hepatocellular carcinoma

Sánchez

González‐Fernández

Crespo

et al. 2018

Journal of Pineal Research

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Disruption of circadian rhythms, which are regulated by the circadian clock machinery, plays an important role in different long-term diseases including hepatocellular carcinoma (HCC). Melatonin has been reported to alleviate promotion and progression of HCC, but the potential contribution of circadian clock modulation is unknown. We investigated the effects of melatonin in mice which received diethylnitrosamine (DEN) (35 mg/kg body weight ip) once a week for 8 weeks. Melatonin was given at 5 or 10 mg kg d ip beginning 4 weeks after the onset of DEN administration and ending at the sacrifice time (10, 20, 30, or 40 weeks). Liver expression of Bmal1, Clock, Npas2, Rorα, and Sirt1 increased, whereas Cry1, Per1, Per2, Per3, CK1ε, Rev-erbα, and Rev-erbβ decreased following DEN administration. Melatonin treatment prevented changes in the expression of clock genes, and this effect was accompanied by an upregulation of the MT1 receptor and reduced levels of the hypoxia-inducible factors Hif-1α and Hif-2α. An increased expression of p21, p53, and PARP1/2, a higher Bax/Bcl-2 ratio, and a lower expression of Cyclin D1, CDK6, HSP70, HSP90, and GRP78 proteins were also observed in melatonin-treated mice. Melatonin significantly potentiated the suppression of proliferation and cell cycle arrest induced by the synthetic REV-ERB agonist SR9009 in human Hep3B cells, and BMAL1 knocking down attenuated the pro-apoptotic and antiproliferative effect of melatonin. Results support a contribution of changes in the circadian clock components to the beneficial effects of melatonin in HCC and highlight the usefulness of strategies modulating the circadian machinery in hepatocarcinogenesis.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine‐induced hepatocellular carcinoma

Sánchez

González‐Fernández

Crespo

et al. 2018

Journal of Pineal Research

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“…In a genome-wide siRNA screen to identify modulators of circadian rhythm, ATF6 siRNA was identified to shorten the circadian period in U2OS cells 31 and is also another potential input point. Here, we did not observe a shortening of period as a result of ER stress induced ATF6 expression; however this is in-line with a recent study which demonstrated a 10 hour shift in circadian rhythm in cancer cells undergoing ER stress 14 . We have shown that ER stress or misfolded proteins can dramatically suppress clock activation in normal fibroblasts, and this poses the question that cancer cells may negate this suppressive role of the UPR on the clock in order to survive.…”

Section: Discussionsupporting

confidence: 92%

Preservation of circadian rhythms by the protein folding chaperone, BiP

Pickard

Chang

Alachkar

et al. 2018

Preprint

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ER stress and dysregulation of collagen synthesis are associated with progression of disease in cancer and fibrosis. Collagen synthesis is co-ordinated with the circadian clock, which curiously in cancer cells, is deregulated by ER stress. We hypothesised that interplay exists between circadian rhythm, collagen synthesis and ER stress in normal cells. Here we show that fibroblasts with ER stress do not demonstrate circadian rhythms in gene expression upon clock-synchronizing time cues. Conversely, overexpression of BiP or treatment with chemical chaperones strengthens the oscillation amplitude of circadian rhythms. The significance of these findings was explored in tendon, where we showed that BiP expression is ramped preemptively prior to a surge in collagen synthesis at night, thereby preventing protein misfolding and ER stress. In turn, we propose, this forestalls activation of the unfolded protein response in order for circadian rhythms to be maintained. Thus, targeting ER stress could be used to modulate circadian rhythm and restore collagen homeostasis in disease.

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“…We further verified that ZNF205‐AS1 increased EGR4 mRNA stability, and therefore up‐regulated EGR4 expression. microRNAs (miRNAs) are well‐known to bind the 3’UTR of target mRNAs and induce the degradation and/or translation inhibition of target mRNAs . The interaction between ZNF205‐AS1 transcript and EGR4 mRNA 3’UTR may protect EGR4 mRNA from miRNAs‐induced degradation, which need further investigation.…”

Section: Discussionmentioning

confidence: 99%

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

Lin

Yang

et al. 2018

J Cellular Molecular Medi

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Accumulating evidences revealed that long noncoding RNAs (lncRNAs) are frequently implicated in non‐small cell lung cancer (NSCLC). Herein, we reported the identification of a novel NSCLC‐associated functional lncRNA ZNF205 antisense RNA 1 (ZNF205‐AS1). ZNF205‐AS1 was increased in NSCLC tissues and cell lines, and associated with poor prognosis of NSCLC patients. Bioinformatics prediction, combined with experimental verification revealed that early growth response 4 (EGR4) directly bound to ZNF205‐AS1 promoter, increased the promoter activity of ZNF205‐AS1, and activated ZNF205‐AS1 transcription. Intriguingly, ZNF205‐AS1 transcript directly interacted with EGR4 mRNA, increased EGR4 mRNA stability, and up‐regulated EGR4 expression via RNA‐RNA interaction. Thus, ZNF205‐AS1 and EGR4 formed a positive feedback loop. Through regulating EGR4, ZNF205‐AS1 activated its own promoter activity. EGR4 was also increased in NSCLC and the expression of ZNF205‐AS1 was significantly positively correlated with EGR4 in NSCLC tissues. Gain‐of‐function and loss‐of‐function assays demonstrated that both ZNF205‐AS1 and EGR4 promoted NSCLC cell growth in vitro and NSCLC tumour growth in vivo. Concurrently depleting ZNF205‐AS1 and EGR4 more significantly repressed NSCLC tumour growth in vivo. Collectively, our study demonstrated that the positive feedback loop between ZNF205‐AS1 and EGR4 promotes NSCLC growth, and implied that targeting this feedback loop may be promising therapeutic strategy for NSCLC.

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A PERK–miR-211 axis suppresses circadian regulators and protein synthesis to promote cancer cell survival

Cited by 93 publications

References 43 publications

RETRACTED: Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine‐induced hepatocellular carcinoma

RETRACTED: Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamine‐induced hepatocellular carcinoma

Preservation of circadian rhythms by the protein folding chaperone, BiP

A positive feedback loop between ZNF205‐AS1 and EGR4 promotes non‐small cell lung cancer growth

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