CircFAT1 sponges miR-375 to promote the expression of Yes-associated protein 1 in osteosarcoma cells

Liu, Gang; Huang, Kai; Jie, Zhiwei; Wu, Yizheng; Chen, Junxin; Chen, Zizheng; Fang, Xiangqian; Shen, Shuying

doi:10.1186/s12943-018-0917-7

Cited by 110 publications

(92 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…After YTHDF2 binds YTHDF3, which carries YAP pre-mRNA containing m 6 A, YTHDF2 presents YAP mRNA to AGO2, and then AGO2 recruits other molecules to form RISC system to facilitate YAP mRNA decay, reducing YAP protein level. It has been recently shown that microRNAs, such as miR-195, miR-375, and others, decrease YAP mRNA levels by binding to YAP 3′UTR [37,38]. Conversely, on the mRNA translation level, recognition and binding of m 6 A by YTHDF1 and YTHDF3 result in enhanced protein synthesis.…”

Section: Discussionmentioning

confidence: 99%

m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC

et al. 2020

View full text Add to dashboard Cite

Background: The importance of mRNA methylation erased by ALKBH5 in mRNA biogenesis, decay, and translation control is an emerging research focus. Ectopically activated YAP is associated with the development of many human cancers. However, the mechanism whereby ALKBH5 regulates YAP expression and activity to inhibit NSCLC tumor growth and metastasis is not clear. Methods: Protein and transcript interactions were analyzed in normal lung cell and NSCLC cells. Gene expression was evaluated by qPCR and reporter assays. Protein levels were determined by immunochemical approaches. Nucleic acid interactions and status were analyzed by immunoprecipitation. Cell behavior was analyzed by standard biochemical tests. The m 6 A modification was analyzed by MeRIP. Results: Our results show that YAP expression is negatively correlated with ALKBH5 expression and plays an opposite role in the regulation of cellular proliferation, invasion, migration, and EMT of NSCLC cells. ALKBH5 reduced m 6 A modification of YAP. YTHDF3 combined YAP pre-mRNA depending on m 6 A modification. YTHDF1 and YTHDF2 competitively interacted with YTHDF3 in an m 6 A-independent manner to regulate YAP expression. YTHDF2 facilitated YAP mRNA decay via the AGO2 system, whereas YTHDF1 promoted YAP mRNA translation by interacting with eIF3a; both these activities are regulated by m 6 A modification. Furthermore, ALKBH5 decreased YAP activity by regulating miR-107/LATS2 axis in an HuR-dependent manner. Further, ALKBH5 inhibited tumor growth and metastasis in vivo by reducing the expression and activity of YAP. Conclusions: The presented findings suggest m 6 A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2-mediated YAP activity in NSCLC. Moreover, effective inhibition of m 6 A modification of ALKBH5 might constitute a potential treatment strategy for lung cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC

et al. 2020

View full text Add to dashboard Cite

show abstract

“…For YAP, the only upstream regulatory transcription factor reported so far is cyclic adenosine monophosphate response element-binding protein (CREB) [46]. In cancer, both YAP and TAZ RNA are frequently increased, but the mechanisms behind this upregulation remain largely elusive and may involve both transcriptional and post-transcriptional mechanisms through suppression of the YAP/TAZ regulatory microRNAs, including miR-15a, miR-141-3p, mir-194, miR-195, miR-375, miR-381, miR-584, miR-125, miR-185, miR-9-3p and miR-129-5p, to name a few [47][48][49][50][51][52][53][54][55][56][57].…”

Section: Transcriptional and Post-transcriptional Regulators Of Yap Amentioning

confidence: 99%

“…MicroRNAs miR-214-3p and miR-23a-5p shed from osteoclasts in exosomes downregulate osteoblast function by targeting upstream YAP regulatory fibroblast growth factor receptor and the YAP/RUNX2 transcriptional complex, respectively [82][83][84]. A circular RNA expressed from the second exon of the FAT Atypical Cadherin 1 gene (circFAT1) was demonstrated to sponge the YAP suppressive microRNA miR-375, thus upregulating YAP1 in osteosarcoma [52]. Vice versa, nuclear YAP/TAZ have also been reported to regulate microRNA biogenesis.…”

Section: Role Of Micrornas In Yap/taz-regulated Circuitriesmentioning

confidence: 99%

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Kovar

Bierbaumer

Radic-Sarikas

2020

Cells

View full text Add to dashboard Cite

YAP and TAZ are intracellular messengers communicating multiple interacting extracellular biophysical and biochemical cues to the transcription apparatus in the nucleus and back to the cell/tissue microenvironment interface through the regulation of cytoskeletal and extracellular matrix components. Their activity is negatively and positively controlled by multiple phosphorylation events. Phenotypically, they serve an important role in cellular plasticity and lineage determination during development. As they regulate self-renewal, proliferation, migration, invasion and differentiation of stem cells, perturbed expression of YAP/TAZ signaling components play important roles in tumorigenesis and metastasis. Despite their high structural similarity, YAP and TAZ are functionally not identical and may play distinct cell type and differentiation stage-specific roles mediated by a diversity of downstream effectors and upstream regulatory molecules. However, YAP and TAZ are frequently looked at as functionally redundant and are not sufficiently discriminated in the scientific literature. As the extracellular matrix composition and mechanosignaling are of particular relevance in bone formation during embryogenesis, post-natal bone elongation and bone regeneration, YAP/TAZ are believed to have critical functions in these processes. Depending on the differentiation stage of mesenchymal stem cells during endochondral bone development, YAP and TAZ serve distinct roles, which are also reflected in bone tumors arising from the mesenchymal lineage at different developmental stages. Efforts to clinically translate the wealth of available knowledge of the pathway for cancer diagnostic and therapeutic purposes focus mainly on YAP and TAZ expression and their role as transcriptional co-activators of TEAD transcription factors but rarely consider the expression and activity of pathway modulatory components and other transcriptional partners of YAP and TAZ. As there is a growing body of evidence for YAP and TAZ as potential therapeutic targets in several cancers, we here interrogate the applicability of this concept to bone tumors. To this end, this review aims to summarize our current knowledge of YAP and TAZ in cell plasticity, normal bone development and bone cancer.Cells 2020, 9, 972 2 of 34 co-activators Yes-associated protein 1 (YAP-1, YAP) and its paralogue, the transcriptional co-activator with PDZ-binding motif (TAZ, WWTR1), which are typically controlled on the post-translational level by upstream regulatory signaling pathways in organ development and tissue homeostasis [2,3]. YAP and TAZ were reported to affect self-renewal and lineage commitment of stem cells [4][5][6][7], while hyperactivation of YAP and TAZ have been linked to cancer growth and metastasis in various tumors [8][9][10]. TAZ levels are elevated in approximately 20% of cancers and drive invasion and metastasis [11,12], while YAP is frequently overexpressed or amplified in cancer and was shown to promote resistance to chemotherapy in oncogene-addicted tumors up...

show abstract

“…The gap between the predicted and functional observed effects of miR-375 knockdown are not entirely unexpected. Several reports provide a possible explanation: long non-coding RNAs, such as TINCR, HNGA1 and CircFAT1 act as a miR-375 sponge [27][28][29]. Thus, the highly expressed miR-375 may be not functionally active in MCC cells.…”

Section: Discussionmentioning

confidence: 99%

Highly expressed miR-375 is not an intracellular oncogene in Merkel cell polyomavirus-associated Merkel cell carcinoma

Fan

Zebisch

Horny

et al. 2019

Preprint

View full text Add to dashboard Cite

201-1836945 2 AbstractPurpose. miR-375 is a highly abundant miRNAs in Merkel cell carcinoma. miR-375 may act as a tumor suppressor or oncogene depending on the cell context. While miR-375 is present as circulating free in the serum of patients with advanced MCC and thus serves as surrogate marker for tumor burden, its function within MCC has not been established.Methods. miR-375 knockdown was performed using miR-375 antagomiRs via lipofectamine transfection or nucleofection in classical MCC cell lines WaGa and PeTa. Viability and both changes in growth characteristics as well as morphology were determined. Genes targeted by miR-375 were predicted using ENCORI; based on these miR-375 regulated signaling pathways were determined by genes ontology (GO) and gene set enrichment analysis (GSEA).Expression of these genes was analyzed by multiplexed RT-qPCR to check the effect of miR-375 knockdown on these signaling pathways.Results. Complete knockdown of miR-375 expression by antagomiRs was only achieved by using nucleofection. This knockdown did not affect cell growth pattern, morphology, or proliferative capacity. miR-375 predicted target genes GO analysis revealed that Hippo signaling and focal adhesion-related genes were likely to be regulated by miR-375. GSEA of gene expression data of MCC cell lines further strengthened the regulation of Focal adhesionrelated genes by miR-375. However, gene expression analysis revealed that miR-375 knockdown had only a limited effect on expression of these pathways related genes. Conclusions.Complete miR-375 knockdown did neither change cell viability, morphology, nor oncogenic signaling pathways; these observations render miR-375 unlikely as intracellular oncogene in MCC cells.

show abstract

CircFAT1 sponges miR-375 to promote the expression of Yes-associated protein 1 in osteosarcoma cells

Cited by 110 publications

References 52 publications

m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC

m6A demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2–mediated YAP activity in NSCLC

The YAP/TAZ Pathway in Osteogenesis and Bone Sarcoma Pathogenesis

Highly expressed miR-375 is not an intracellular oncogene in Merkel cell polyomavirus-associated Merkel cell carcinoma

Contact Info

Product

Resources

About