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 Foxo3 protein. As a result, cell apoptosis was induced by upregulation of the Foxo3 downstream target PUMA.
Most RNAs generated by the human genome have no protein-coding ability and are termed non-coding RNAs. Among these include circular RNAs, which include exonic circular RNAs (circRNA), mainly found in ...the cytoplasm, and intronic RNAs (ciRNA), predominantly detected in the nucleus. The biological functions of circular RNAs remain largely unknown, although ciRNAs have been reported to promote gene transcription, while circRNAs may function as microRNA sponges. We demonstrate that the circular RNA circ-Foxo3 was highly expressed in non-cancer cells and were associated with cell cycle progression. Silencing endogenous circ-Foxo3 promoted cell proliferation. Ectopic expression of circ-Foxo3 repressed cell cycle progression by binding to the cell cycle proteins cyclin-dependent kinase 2 (also known as cell division protein kinase 2 or CDK2) and cyclin-dependent kinase inhibitor 1 (or p21), resulting in the formation of a ternary complex. Normally, CDK2 interacts with cyclin A and cyclin E to facilitate cell cycle entry, while p21works to inhibit these interactions and arrest cell cycle progression. The formation of this circ-Foxo3-p21-CDK2 ternary complex arrested the function of CDK2 and blocked cell cycle progression.
Yap is the key component of Hippo pathway which plays crucial roles in tumorigenesis. Inhibition of Yap activity could promote apoptosis, suppress proliferation, and restrain metastasis of cancer ...cells. However, how Yap is regulated is not fully understood. Here, we reported Yap being negatively regulated by its circular RNA (circYap) through the suppression of the assembly of Yap translation initiation machinery. Overexpression of circYap in cancer cells significantly decreased Yap protein but did not affect its mRNA levels. As a consequence, it remarkably suppressed proliferation, migration and colony formation of the cells. We found that circYap could bind with Yap mRNA and the translation initiation associated proteins, eIF4G and PABP. The complex containing overexpressed circYap abolished the interaction of PABP on the poly(A) tail with eIF4G on the 5'-cap of the Yap mRNA, which functionally led to the suppression of Yap translation initiation. Individually blocking the binding sites of circYap on Yap mRNA or respectively mutating the binding sites for PABP and eIF4G derepressed Yap translation. Significantly, breast cancer tissue from patients in the study manifested dysregulation of circYap expression. Collectively, our study uncovered a novel molecular mechanism in the regulation of Yap and implicated a new function of circular RNA, supporting the pursuit of circYap as a potential tool for future cancer intervention.
Circular RNAs are a subclass of non-coding RNAs detected within mammalian cells. This study was designed to test the roles of a circular RNA circ-Foxo3 in senescence using in vitro and in vivo ...approaches.
Using the approaches of molecular and cellular biology, we show that a circular RNA generated from a member of the forkhead family of transcription factors, Foxo3, namely circ-Foxo3, was highly expressed in heart samples of aged patients and mice, which was correlated with markers of cellular senescence. Doxorubicin-induced cardiomyopathy was aggravated by ectopic expression of circ-Foxo3 but was relieved by silencing endogenous circ-Foxo3. We also found that silencing circ-Foxo3 inhibited senescence of mouse embryonic fibroblasts and that ectopic expression of circ-Foxo3 induced senescence. We found that circ-Foxo3 was mainly distributed in the cytoplasm, where it interacted with the anti-senescent protein ID-1 and the transcription factor E2F1, as well as the anti-stress proteins FAK and HIF1α.
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.
Circular RNAs represent a large class of non-coding RNAs that are extensively expressed in mammals. However, the functions of circular RNAs are largely unknown. We recently reported that the circular ...RNA circ-Ccnb1 could bind with H2AX in p53 mutant cells and suppressed mutant p53 in tumor progression. Here we found that circ-Ccnb1 could interact with both Ccnb1 and Cdk1 proteins. Normally, Ccnb1 and Cdk1 proteins form a complex, allowing Ccnb1 to function as an all-or-none switch for cell mitosis. The interaction of circ-Ccnb1 with Ccnb1 and Cdk1 proteins dissociated the formation of Ccnb1-Cdk1 complex, by forming a large complex containing circ-Ccnb1, Ccnb1 and Cdk1. Formation of this large complex may occur in cytosol and nuclei, and Ccnb1 loses its roles in enhancing cell migration, invasion, proliferation and survival. In vivo, ectopic delivery of circ-Ccnb1 inhibited tumor growth and extended mouse viability. These results have added another layer of mechanisms for circ-Ccnb1 to regulate tumor progression in vitro and in vivo.
•circ-Ccnb1 interacts with CCNB1 and CDK1 dissociating the formation of CCNB1-CDK1 complex.•The large complex may translocate to cytosol and nuclei.•CCNB1 loses its roles in enhancing cell migration, invasion, proliferation and survival.•Delivery of circ-CCNB1 inhibits tumor growth and extends mouse viability in vivo.
Circular RNAs have been identified as naturally occurring RNAs that are highly represented in the eukaryotic transcriptome. Although a large number of circRNAs have been reported, circRNA functions ...remain largely unknown. CircRNAs can function as miRNA sponges, thereby reducing their ability to target mRNAs. We hypothesize that circRNAs may bind, store, sort, and sequester proteins to particular subcellular locations, and act as dynamic scaffolding molecules that modulate protein-protein interactions. Here, we review the biological implication and function of circRNA-protein interaction, and reveal a dynamic model of the interaction in various tissues, development stages and physiological conditions. Improved techniques to identify and characterize the dynamic RNA-protein interactions may elucidate the molecular mechanisms associated with the expression and functional diversity of circRNAs.
MicroRNAs (miRNA) precursor (pre-miRNA) molecules can be processed to release a miRNA/miRNA* duplex. In the canonical model of miRNA biogenesis, one strand of the duplex is thought to be the ...biologically active miRNA, whereas the other strand is thought to be inactive and degraded as a carrier or passenger strand called miRNA* (miRNA star). However, recent studies have revealed that miRNA* strands frequently play roles in the regulatory networks of miRNA target molecules. Our recent study indicated that miR-17 transgenic mice could abundantly express both the mature miR-17-5p and the passenger strand miR-17-3p. Here, we showed that miR-17 enhanced prostate tumor growth and invasion by increasing tumor cell proliferation, colony formation, cell survival and invasion. miRNA target analysis showed that both miR-17-5p and miR-17-3p repressed TIMP metallopeptidase inhibitor 3 (TIMP3) expression. Silencing with small interfering RNA against TIMP3 promoted cell survival and invasion. Ectopic expression of TIMP3 decreased cell invasion and cell survival. Our results demonstrated that mature miRNA can function coordinately with its passenger strand, enhancing the repressive ability of a miRNA by binding the same target. Within an intricate regulatory network, this may be among the mechanisms by which miRNA can augment their regulatory capacity.
From manufacture to disposal, the interaction of graphdiyne based nanomaterials with living organisms is inevitable and crucial. However, the cytotoxic properties of this novel carbon nanomaterial ...are rarely investigated, and the mechanisms behind their cytotoxicity are totally unknown. In this study, the antibacterial activity of graphdiyne (GDY) and graphdiyne oxide (GDYO) is reported. GDY is capable of inhibiting broad‐spectrum bacterial growth while exerting moderate cytotoxicity on mammalian cells. In comparison, GDYO exhibits lower antibacterial activity than that of GDY. Then an alterable, synergetic antibacterial mechanism of GDY, involving wrapping bacterial membrane, membrane insertion and disruption, and reactive oxygen species generation is demonstrated, while the differential gene expression analysis indicates that GDY could only alter the bacterial metabolism slightly and the oxidative stress route may be a minor bactericidal factor. The investigation of the antibacterial behaviors of GDY based nanomaterials may provide useful guidelines for the future design and application of this novel molecular allotrope of carbon.
This work discloses the antibacterial mechanism of graphdiyne (GDY) and GDY oxide. The excellent bactericidal potency of GDY is primarily associated with physical destruction. The capability of GDY to wrap bacteria through physical adsorption and pierce bacterial membranes with sharp edges, results in leakage of intracellular substances and bacterial death. ROS‐induced oxidative stress serves a supporting role on bacterial inhibition.
Circular RNAs (circRNAs) are a subclass of noncoding RNAs widely expressed in mammalian cells. We report here the tumorigenic capacity of a circRNA derived from angiomotin-like1 (circ-Amotl1). ...Circ-Amotl1 is highly expressed in patient tumor samples and cancer cell lines. Single-cell inoculations using circ-Amotl1-transfected tumor cells showed a 30-fold increase in proliferative capacity relative to control. Agarose colony-formation assays similarly revealed a 142-fold increase. Tumor-take rate in nude mouse xenografts using 6-day (219 cells) and 3-day (9 cells) colonies were 100%, suggesting tumor-forming potential of every cell. Subcutaneous single-cell injections led to the formation of palpable tumors in 41% of mice, with tumor sizes >1 cm
in 1 month. We further found that this potent tumorigenicity was triggered through interactions between circ-Amotl1 and c-myc. A putative binding site was identified in silico and tested experimentally. Ectopic expression of circ-Amotl1 increased retention of nuclear c-myc, appearing to promote c-myc stability and upregulate c-myc targets. Expression of circ-Amotl1 also increased the affinity of c-myc binding to a number of promoters. Our study therefore reveals a novel function of circRNAs in tumorigenesis, and this subclass of noncoding RNAs may represent a potential target in cancer therapy.
Display omitted
•PdFe/GDY was synthesized by a facile hydrothermal method.•PdFe/GDY shows intrinsic peroxidase-like activity.•A sensitive chemo/biosensing assay for GSH with ultra-low limit of ...detection.•PdFe/GDY exhibits excellent antibacterial efficiency in wound disinfection.
Multifunctional enzymatic nanomaterials (nanozymes) with good biocompatibility, strong enzymatic activity, and substrate specificity are the desired alternatives to natural enzymes. Here, the design of a peroxidase mimetic nanozyme capable of detecting and depleting glutathione (GSH) in the bacterial cells is presented. The nanozyme palladium-iron nanostructure decorated graphdiyne nanosheet (PdFe/GDY) was prepared by a facile hydrothermal approach. It can efficiently catalyze the decomposition of H2O2 to produce •OH by a peroxidase-like mechanism. Surprisingly, the PdFe/GDY nanozymes can detect GSH in bacteria with excellent specificity and ultra-low detection limit of 24.45 nM. Moreover, the PdFe/GDY nanozymes can consume GSH for bacterial disinfection with killing efficacy > 99.99%, promote wound healing and do not cause significant toxicity in vitro and in vivo. To our knowledge, this is the first example of a GDY-based nanozyme biosensor and antibacterial agent. Collectively, this work would be indicative to construct GDY-based nanozymes in clinical diagnosis and sterilization.
PDF
