Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses

Du, William W.; Yang, Weining; Chen, Yu; Wu, Zhongkai; Foster, F. Stuart; Yang, Zhen-Guo; Li, Xiangmin; Yang, Burton B.

doi:10.1093/eurheartj/ehw001

Cited by 453 publications

(507 citation statements)

References 25 publications

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“…Du et al discovered that the role of Foxo3 circular RNA (circ-Foxo3) in cellular senescence was to retain the anti-senescent protein ID-1, the transcription factor E2F1, and the anti-stress proteins FAK and HIF1a in the cytoplasm, thus inhibiting their functions in anti-stress and anti-senescent processes. 25 Strikingly, in their study, in vivo delivery of circFoxo3 targeted siRNA into mouse embryonic fibroblasts and primary cardiac myocytes resulted in lower levels of circ-Foxo3 expression and b-gal staining, which is a standard marker for senescence, suggesting a potential therapeutic approach for myocardial protection. While circ-Foxo3 promotes cardiac cell death, a circular RNA (HRCR) was found to protect the heart from pathological hypertrophy and heart failure by sequestering and inhibiting miR-223 activity as an endogenous miRNA sponge.…”

Section: Cardiovascular Diseasementioning

confidence: 99%

“…circFoxo3 was found to interact with the anti-senescence proteins ID1 and E2F1 and the anti-stress proteins FAK and HIF1a, causing them to be retained in the cytoplasm. 25 The effect of circ-Foxo3 on the subcellular translocation of these proteins blocked their anti-senescent function. Another study by the same research group showed that circ-Foxo3 could also bind to the cell cycle proteins cyclin-dependent kinase 2 (CDK2) and cyclin-dependent kinase inhibitor 1 (p21), resulting in the formation of a ternary complex.…”

Section: Protein Interactionmentioning

confidence: 99%

“…27 Another study that employed in vivo delivery of siRNA-targeting endogenous circ-Foxo3 showed that it abrogated the effect of doxorubicin-induced cardiomyopathy, suggesting a potential therapeutic approach for myocardial protection. 25 …”

Section: Clinical Implication Of Human Circrnasmentioning

confidence: 99%

“…Genome-wide RNA-sequencing analyses have now identified a considerable number of circRNAs derived from backsplicing. Although they are generally expressed at low levels, increasing evidence has shown that circRNAs are linked to physiological development 15 and different diseases, such as neurological dystrophy, 21 cardiovascular diseases, [22][23][24][25] and cancer. [26][27][28] Recently, circRNAs have also been shown to be enriched and stable in plasma, 29 saliva, 30 and even in serum exosomes, 31 indicating the potential of circRNAs as readable biomarkers.…”

Section: Introductionmentioning

confidence: 99%

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The emerging role and clinical implication of human exonic circular RNA

Lyu

Huang

2016

RNA Biology

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Circular RNA from backspliced exons (or exonic circular RNA, circRNA) is a type of covalently closed noncolinear RNA that was recently rediscovered in eukaryotes. Although circRNAs are often expressed at low levels, emerging evidence indicates that many circRNAs are linked to physiological development and various diseases. Notably, circRNAs have been shown to serve as oncogenic stimuli or tumor suppressors in cancer. circRNAs may regulate gene expression through different mechanisms. In addition, circRNAs have been shown to be useful as biomarkers of diseases due to their stability, specific expression and relation to diseases both in cells and in extracellular fluid. This review summarizes current knowledge of human circRNAs and discusses the emerging role and clinical implication of these multifarious transcripts.

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Section: Cardiovascular Diseasementioning

confidence: 99%

Section: Protein Interactionmentioning

confidence: 99%

Section: Clinical Implication Of Human Circrnasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The emerging role and clinical implication of human exonic circular RNA

Lyu

Huang

2016

RNA Biology

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“…9 Recently, we showed that the circular RNA circ-Foxo3 could function by binding to proteins in related signal pathways. 10,11 In the present study, we used computational approach to elucidate the interaction of circ-Foxo3 with MDM2 and p53. The RING-finger domain in the carboxyl terminal of the MDM2 is known to bind RNA specifically in a sequence-specific manner, 12 whereas p53 interacts with RNA via its C-terminal regulatory domain.…”

mentioning

confidence: 99%

Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity

et al. 2016

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Circular RNAs are a class of non-coding RNAs that are receiving extensive attention. Despite reports showing circular RNAs acting as microRNA sponges, the biological functions of circular RNAs remain largely unknown. We show that in patient tumor samples and in a panel of cancer cells, circ-Foxo3 was minimally expressed. Interestingly, during cancer cell apoptosis, the expression of circ-Foxo3 was found to be significantly increased. We found that silencing endogenous circ-Foxo3 enhanced cell viability, whereas ectopic expression of circ-Foxo3 triggered stress-induced apoptosis and inhibited the growth of tumor xenografts. Also, expression of circ-Foxo3 increased Foxo3 protein levels but repressed p53 levels. By binding to both, circ-Foxo3 promoted MDM2-induced p53 ubiquitination and subsequent degradation, resulting in an overall decrease of p53. With low binding affinity to Foxo3 protein, circ-Foxo3 prevented MDM2 from inducing Foxo3 ubiquitination and degradation, resulting in increased levels of Circular RNAs are a large class of non-coding RNAs that are circularized by joining free 3'-to 5'-ends, forming a circular structure. 1-4Although circular RNAs were initially characterized over 30 years ago, their functions in mammalian cells are still largely unknown. Most circular RNAs are predominantly found in the cytoplasm and contain exons, known as circRNAs.5 A relatively smaller group of circular RNAs that contain both exons and introns are known as EIciRNAs, and are predominantly found in the nucleus. 6 Recent studies have indicated that some circular RNAs contain miRNA binding sites and may function as sponges to arrest miRNA functions. 7,8 It has further been reported that EIciRNAs increase the transcription of their parental genes.9 Recently, we showed that the circular RNA circ-Foxo3 could function by binding to proteins in related signal pathways. 10,11 In the present study, we used computational approach to elucidate the interaction of circ-Foxo3 with MDM2 and p53. The RING-finger domain in the carboxyl terminal of the MDM2 is known to bind RNA specifically in a sequence-specific manner, 12 whereas p53 interacts with RNA via its C-terminal regulatory domain. 13 Our study comprised of computer-aided RNA structure modeling of circ-Foxo3 employing minimum free energy algorithm and machine translation system followed by its molecular interaction with MDM2 (RING-finger domain) and p53 (C-terminal regulatory domain) that includes docking, scoring, clustering, and refinement of the most promising models. The interaction was further confirmed by an approach of molecular experiments to explicate the biological functions of circ-Foxo3. ResultsDecreased expression of circ-Foxo3 in tumors and cancer cells. Downregulation of Foxo3 is often observed in cancer development.14,15 Both circ-Foxo3 and Foxo3 mRNA are encoded by the FOXO3 gene. 16 We found that the levels of circ-Foxo3 in tumor specimen were significantly lower than in the adjacent benign tissue (Figure 1a). We examined circ-Foxo3 expression and detected s...

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circCIMT Silencing Promotes Cadmium‐Induced Malignant Transformation of Lung Epithelial Cells Through the DNA Base Excision Repair Pathway

Chen

Cui

et al. 2023

Advanced Science

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Changes in gene expression in lung epithelial cells are detected in cancer tissues during exposure to pollutants, highlighting the importance of gene‐environmental interactions in disease. Here, a Cd‐induced malignant transformation model in mouse lungs and bronchial epithelial cell lines is constructed, and differences in the expression of non‐coding circRNAs are analyzed. The migratory and invasive abilities of Cd‐transformed cells are suppressed by circCIMT. A significant DNA damage response is observed after exposure to Cd, which increased further following circCIMT‐interference. It is found that APEX1 is significantly down‐regulated following Cd exposure. Furthermore, it is demonstrated that circCIMT bound to APEX1 during Cd exposure to mediate the DNA base excision repair (BER) pathway, thereby reducing DNA damage. In addition, simultaneous knockdown of both circCIMT and APEX1 promotes the expression of cancer‐related genes and malignant transformation after long‐term Cd exposure. Overall, these findings emphasis the importance of genetic‐epigenetic interactions in chemical‐induced cancer transformation.

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Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses

Abstract: We conclude that ID-1, E2F1, FAK, and HIF1α interact with circ-Foxo3 and are retained in the cytoplasm and could no longer exert their anti-senescent and anti-stress roles, resulting in increased cellular senescence.

Cited by 453 publications

References 25 publications

The emerging role and clinical implication of human exonic circular RNA

The emerging role and clinical implication of human exonic circular RNA

Induction of tumor apoptosis through a circular RNA enhancing Foxo3 activity

circCIMT Silencing Promotes Cadmium‐Induced Malignant Transformation of Lung Epithelial Cells Through the DNA Base Excision Repair Pathway

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