Abstract:Accumulated evidence indicates that circadian genes regulate cell damage and senescence in most mammals. Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) regulate longevity in many organisms. However, the specific mechanisms of the relationship between the circadian clock and the two stress processes in organisms are poorly understood. Here, we show that Clock-mediated Pdia3 expression is required to sustain reactive oxidative reagents and ER stress. First, ER stress and ROS are strongly act… Show more
“…4m, n ). Thus, we conclude that the Yap1/NF-κB axis represses the PERK and ATF6 arms of the UPR, which are associated with clock activity and survival during differentiation 29 , 54 – 56 . Fig.…”
Section: Resultsmentioning
confidence: 73%
“…Recent studies have established a link between the UPR and the circadian clock 29 , 54 . SAHA/JQ1 treatment upregulates multiple UPR target genes based on microarray analyses of KP cells (Fig.…”
Terminal differentiation opposes proliferation in the vast majority of tissue types. As a result, loss of lineage differentiation is a hallmark of aggressive cancers, including soft tissue sarcomas (STS). Consistent with these observations, undifferentiated pleomorphic sarcoma (UPS), an STS subtype devoid of lineage markers, is among the most lethal sarcomas in adults. Though tissue-specific features are lost in these mesenchymal tumors they are most commonly diagnosed in skeletal muscle, and are thought to develop from transformed muscle progenitor cells. We have found that a combination of HDAC (Vorinostat) and BET bromodomain (JQ1) inhibition partially restores differentiation to skeletal muscle UPS cells and tissues, enforcing a myoblast-like identity. Importantly, differentiation is partially contingent upon downregulation of the Hippo pathway transcriptional effector Yes-associated protein 1 (YAP1) and nuclear factor (NF)-κB. Previously, we observed that Vorinostat/JQ1 inactivates YAP1 and restores oscillation of NF-κB in differentiating myoblasts. These effects correlate with reduced tumorigenesis, and enhanced differentiation. However, the mechanisms by which the Hippo/NF-κB axis impact differentiation remained unknown. Here, we report that YAP1 and NF-κB activity suppress circadian clock function, inhibiting differentiation and promoting proliferation. In most tissues, clock activation is antagonized by the unfolded protein response (UPR). However, skeletal muscle differentiation requires both Clock and UPR activity, suggesting the molecular link between them is unique in muscle. In skeletal muscle-derived UPS, we observed that YAP1 suppresses PERK and ATF6-mediated UPR target expression as well as clock genes. These pathways govern metabolic processes, including autophagy, and their disruption shifts metabolism toward cancer cell-associated glycolysis and hyper-proliferation. Treatment with Vorinostat/JQ1 inhibited glycolysis/MTOR signaling, activated the clock, and upregulated the UPR and autophagy via inhibition of YAP1/NF-κB. These findings support the use of epigenetic modulators to treat human UPS. In addition, we identify specific autophagy, UPR, and muscle differentiation-associated genes as potential biomarkers of treatment efficacy and differentiation.
“…4m, n ). Thus, we conclude that the Yap1/NF-κB axis represses the PERK and ATF6 arms of the UPR, which are associated with clock activity and survival during differentiation 29 , 54 – 56 . Fig.…”
Section: Resultsmentioning
confidence: 73%
“…Recent studies have established a link between the UPR and the circadian clock 29 , 54 . SAHA/JQ1 treatment upregulates multiple UPR target genes based on microarray analyses of KP cells (Fig.…”
Terminal differentiation opposes proliferation in the vast majority of tissue types. As a result, loss of lineage differentiation is a hallmark of aggressive cancers, including soft tissue sarcomas (STS). Consistent with these observations, undifferentiated pleomorphic sarcoma (UPS), an STS subtype devoid of lineage markers, is among the most lethal sarcomas in adults. Though tissue-specific features are lost in these mesenchymal tumors they are most commonly diagnosed in skeletal muscle, and are thought to develop from transformed muscle progenitor cells. We have found that a combination of HDAC (Vorinostat) and BET bromodomain (JQ1) inhibition partially restores differentiation to skeletal muscle UPS cells and tissues, enforcing a myoblast-like identity. Importantly, differentiation is partially contingent upon downregulation of the Hippo pathway transcriptional effector Yes-associated protein 1 (YAP1) and nuclear factor (NF)-κB. Previously, we observed that Vorinostat/JQ1 inactivates YAP1 and restores oscillation of NF-κB in differentiating myoblasts. These effects correlate with reduced tumorigenesis, and enhanced differentiation. However, the mechanisms by which the Hippo/NF-κB axis impact differentiation remained unknown. Here, we report that YAP1 and NF-κB activity suppress circadian clock function, inhibiting differentiation and promoting proliferation. In most tissues, clock activation is antagonized by the unfolded protein response (UPR). However, skeletal muscle differentiation requires both Clock and UPR activity, suggesting the molecular link between them is unique in muscle. In skeletal muscle-derived UPS, we observed that YAP1 suppresses PERK and ATF6-mediated UPR target expression as well as clock genes. These pathways govern metabolic processes, including autophagy, and their disruption shifts metabolism toward cancer cell-associated glycolysis and hyper-proliferation. Treatment with Vorinostat/JQ1 inhibited glycolysis/MTOR signaling, activated the clock, and upregulated the UPR and autophagy via inhibition of YAP1/NF-κB. These findings support the use of epigenetic modulators to treat human UPS. In addition, we identify specific autophagy, UPR, and muscle differentiation-associated genes as potential biomarkers of treatment efficacy and differentiation.
“…Also, clock-responsive elements (E-box or E-box-like) are found in the promoter regions of antioxidative genes. Furthermore, animals deficient in clock proteins show increased reactive oxygen species generation and decreased antioxidative enzyme activity [ 9 – 11 ].…”
Parkinson's disease (PD) is the second most common neurodegenerative disease and is known to involve circadian dysfunction and oxidative stress. Although antioxidative defense is regulated by the molecular circadian clock, few studies have examined their function in PD and their regulation by silent information regulator 1 (SIRT1). We hypothesize that reduced antioxidative activity in models of PD results from dysfunction of the molecular circadian clock via the SIRT1 pathway. We treated rats and SH-SY5Y cells with 6-hydroxydopamine (6-OHDA) and measured the expression of core circadian clock and associated nuclear receptor genes using real-time quantitative PCR as well as levels of SIRT1, brain and muscle Arnt-like protein 1 (BMAL1), and acetylated BMAL1 using Western blotting. We found that 6-OHDA treatment altered the expression patterns of clock and antioxidative molecules in vivo and in vitro. We also detected an increased ratio of acetylated BMAL1:BMAL1 and a decreased level of SIRT1. Furthermore, resveratrol, an activator of SIRT1, decreased the acetylation of BMAL1 and inhibited its binding with CRY1, thereby reversing the impaired antioxidative activity induced by 6-OHDA. These results suggest that a dysfunctional circadian clock contributes to an abnormal antioxidative response in PD via a SIRT1-dependent BMAL1 pathway.
“…Cytoplasmic dynein 1 (DYNLL1), acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules, is also reported to enhance the intracellular transport of porcine circovirus type 2 (PCV2) 31 . Circadian clocks control the processes of diseases such as inflammation, aging, virus replication and the severity of infections [32][33][34] . FBXL3 is reported to bind to a core circadian protein cryptochrome 2 (Cry2) to promote its degradation.…”
The COVID-19 pandemic has infected millions of people and overwhelmed many health systems globally. Our study is to identify differentially expressed genes (DEGs) and associated biological processes of COVID-19 using a bioinformatics approach to elucidate their potential pathogenesis. The gene expression profiles of the GSE152075 datasets were originally produced by using the high-throughput Illumina NextSeq 500. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed to identify functional categories and biochemical pathways. GO and KEGG results suggested that several biological pathways such as Fatty acid metabolism and Cilium morphogenesis are mostly involved in the development of COVID-19. Moreover, several genes are critical for virus invasion and adhesion including FLOC, DYNLL1, FBXL3, and FBXW11 and show significant differences in COVID-19 patients. Thus, our study provides further insights into the underlying pathogenesis of COVID-19.
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