Enhanced breast cancer progression by mutant p53 is inhibited by the circular RNA circ-Ccnb1

Fang, Ling; Du, William W.; Lyu, Jingjing; Dong, Jun; Zhang, Chao; Yang, Weining; He, Alina; Kwok, Yat Sze Sheila; Ma, Jian; Wu, Nan; Li, Feiya; Awan, Faryal Mehwish; He, Chengyan; Yang, Bing; Peng, Chun; Mackay, Helen; Yee, Albert; Yang, Burton B.

doi:10.1038/s41418-018-0115-6

Cited by 109 publications

(95 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1a). We also examined the levels of circYap relative to several known cirRNAs and found that its level was lower than high abundant cirRNAs circHIPK3 and circCDYL [25], but higher than the recently reported tumor suppressor circCcnb1 [26] (Fig. S1a).…”

Section: Yap Protein Expression Was Antagonized By Circyapmentioning

confidence: 92%

Translation of yes-associated protein (YAP) was antagonized by its circular RNA via suppressing the assembly of the translation initiation machinery

et al. 2019

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Yap Protein Expression Was Antagonized By Circyapmentioning

confidence: 92%

Translation of yes-associated protein (YAP) was antagonized by its circular RNA via suppressing the assembly of the translation initiation machinery

et al. 2019

Self Cite

View full text Add to dashboard Cite

show abstract

“…With regard to the mechanism, circPVT1 expression is transcriptionally enhanced by the mut-p53/YAP/TEAD complex, hence circPVT1 acts as an oncogene regulating cell proliferation in HNSCC [99]. Circ-Ccnb1 breast [99,100] In breast cancer cells, it has been shown that wt-p53 enhanced circ-Ccnb1 expression, whereas repression of wt-p53 or the expression of mutated p53 repressed circ-Ccnb1 expression levels (Table 4) [100].…”

Section: Mutant P53 and Circular Rnasmentioning

confidence: 99%

“…Analysis of circ-Ccnb1 levels in samples from breast cancer patients showed that the subgroup expressing mut-p53 proteins displayed significantly lower levels of circ-Ccnb1, compared to the p53 wild-type samples [100]. An in vivo xenograft experiment showed that the ectopic expression of circ-Ccnb1 significantly repressed tumor growth [100]. Therefore, circ-Ccnb1 can be considered a tumor suppressor that is down-regulated by mut-p53 proteins and which could be an excellent target that could be reactivated by targeted therapies.…”

Section: Mutant P53 and Circular Rnasmentioning

confidence: 99%

“…With regard to the mechanism, the circular RNA circ-Ccnb1 dissociates CyclinB1/Cdk1 mitotic complex suppressing cell invasion and tumorigenesis [101]. What has been said so far, is that mut-p53 directly promotes high proliferation, by inducing the transcription of the ccnb1 and cdk1 genes [16] and indirectly supporting the maintenance of the expression of its transcriptional cofactors such as YAP [18] and by inhibiting biomolecules that destabilize mitotic pathways [100,101].…”

Section: Mutant P53 and Circular Rnasmentioning

confidence: 99%

See 1 more Smart Citation

The Impact of Mutant p53 in the Non-Coding RNA World

Agostino

2020

Biomolecules

View full text Add to dashboard Cite

Long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), micro RNAs (miRNAs), and extracellular RNAs (exRNAs) are new groups of RNAs with regulation activities that have low or no protein-coding ability. Emerging evidence suggests that deregulated expression of these non-coding RNAs is associated with the induction and progression of diverse tumors throughout epigenetic, transcriptional, and post-transcriptional modifications. A consistent number of non-coding RNAs (ncRNAs) has been shown to be regulated by p53, the most important tumor suppressor of the cells frequently mutated in human cancer. It has been shown that some mutant p53 proteins are associated with the loss of tumor suppressor activity and the acquisition of new oncogenic functions named gain-of-function activities. In this review, we highlight recent lines of evidence suggesting that mutant p53 is involved in the expression of specific ncRNAs to gain oncogenic functions through the creation of a complex network of pathways that influence each other.Biomolecules 2020, 10, 472 2 of 15 heterotetrameric mut-p53/wt-p53 complex can inhibit the function of the remaining wt-p53 in tumor suppression [8,9]. Most of the missense mutations occur in the p53 DNA-binding region and can be classified as either contact mutations (as p53R248 and p53R273 interfere directly with DNA binding) or conformational mutations (as p53R175 induces local or global conformational distortions) [5,9].Six hotspot mutations are the most represented in the cancers. These include R175, G245, R248, R249, R273, and R282, which make up about 30% of all mutations in TP53 covering all human cancer types [8][9][10]. However, due to cancer genome sequencing tools, many other different TP53 mutations have been discovered. mut-p53 GOF has been demonstrated by numerous cell-based experiments such as by ectopic expression of mut-p53 proteins in p53-null human tumor cells or knockdown of endogenous mut-p53 in cells containing only one allele of mutant p53, as well as in mutant p53 knock-in mouse models [5,[8][9][10]. Genome sequencencing has highlighted that more than 91% of TP53-mutant cancers exhibit loss of the second allele (LOH) by mutation or DNA deletion [11].Many mut-p53 GOF activities have been identified as tumor cell proliferation, survival, migration and invasion, enhancing chemoresistance, disrupting proper tissue architecture, inducing cancer metabolism (Warburg effect and lipid metabolism), and increasing genomic instability and mitochondrial dysfunction [5,[10][11][12][13][14][15] (Figure 1).

show abstract

“…Although circRNAs have attracted increasing attention, our understanding of their functions is still limited . They appear to control brain function by titrating miRNAs (Piwecka et al, 2017), interacting with RNA-binding domains to influence cancer development (Fang et al, 2018), and protecting mRNAs from degradation (Zhu et al, 2019). They can also be biomarkers of cancer (Li Y. et al, 2015), ciRNAs and EIciRNAs are localized in the nucleus, where they promote the transcription of their parent genes .…”

Section: Introductionmentioning

confidence: 99%

Structure, Regulation, and Function of Linear and Circular Long Non-Coding RNAs

Qin

Zhang

2020

Front. Genet.

View full text Add to dashboard Cite

Long non-coding RNAs (lncRNAs), including linear lncRNAs and circular RNAs (circRNAs), exhibit a surprising range of structures. Linear lncRNAs and circRNAs are generated by different pathways. Linear lncRNAs perform functions that depend on their specific sequences, transcription, and DNA elements of their gene loci. In some cases, linear lncRNAs contain a short open reading frame encoding a peptide. circRNAs are covalently closed RNAs with tissue-specific and cell-specific expression patterns that have recently been extensively investigated. Pioneering work focusing on their biogenesis and functional characterization indicates that circRNAs regulate cell development via multiple mechanisms and play critical roles in the immune system. Furthermore, circRNAs in exosomes function on target cells. As with linear lncRNAs, specific circRNAs can also be translated. In this review, we summarize current understanding and highlight the diverse structure, regulation, and function of linear lncRNAs and circRNAs.

show abstract

Enhanced breast cancer progression by mutant p53 is inhibited by the circular RNA circ-Ccnb1

Cited by 109 publications

References 49 publications

Translation of yes-associated protein (YAP) was antagonized by its circular RNA via suppressing the assembly of the translation initiation machinery

Translation of yes-associated protein (YAP) was antagonized by its circular RNA via suppressing the assembly of the translation initiation machinery

The Impact of Mutant p53 in the Non-Coding RNA World

Structure, Regulation, and Function of Linear and Circular Long Non-Coding RNAs

Contact Info

Product

Resources

About