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A novel lncRNA MTAR1 promotes cancer development through IGF2BPs mediated post-transcriptional regulation of c-MYC

Abstract

Abnormal translation of the MYC proto-oncogene is a hallmark of the initiation and maintenance of tumorigenesis. However, the molecular mechanism underlying increased MYC protein levels in certain cancer types without a corresponding increase in MYC mRNA levels is unclear. Here, we identified a novel lncRNA, MTAR1, which is critical for post-transcriptional regulation of MYC-induced tumorigenesis. MTAR1 is essential for recruiting IGF2BPs into PABP1-mediated liquid–liquid phase separation (LLPS) complexes and facilitates IGF2BPs-mediated MYC mRNA translation. MTAR1 enhanced binding between IGF2BPs and PABP1, thereby promoting MYC mRNA stability and increased MYC mRNA translation. In summary, MTAR1 is a novel MYC-related lncRNA that contributes to tumor progression by enhancing MYC translation through mediating PABP1/IGF2BPs liquid–liquid phase separation.

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Fig. 1: TCONS_02256997 expression is highly correlated with c-MYC translation.
Fig. 2: MTAR1 is an oncogenic lncRNA and may affect human cancer cell phenotype through the MYC pathway.
Fig. 3: MTAR1 is an oncogenic lncRNA associated with tumorigenesis.
Fig. 4: MTAR1 interacts with protein IGF2BPs and PABP1 that may positively regulate MYC translation.
Fig. 5: PABP1 can facilitate LLPS and complex with IGF2BP.
Fig. 6: MTAR1 reinforces the interaction between PABP1 and IGF2BP2, thus promotes MYC translation.

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Acknowledgements

We thank Dr. Kyle Vaughn Laster for editing this manuscript. We thank Liwen Bianji, Edanz Editing China (www.liwenbianji.cn/ac) and professor Andrew Dingley, for editing this manuscript. We thank BioRender.com for their software that enabled us to generate the graphic abstract.

Funding

This research is supported by the National Natural Science Foundations of China (No. 81802876), the Project of Science and Technology of the Henan Province for Tackling Key Problems (182102310128) and the National Natural Science Foundations of China (Nos. 81872335, 81802875, 81972639).

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Contributions

YFG, first author, main implementer, took participate into all parts of work of this manuscript. MJ, co-first author, main implementer, took most part of work of this manuscript. FQG, participated in designing and performing in vitro experiments. XJL, took part in performing cell culture experiments and formal analysis. QZ, participated in most in vitro experiments. SY, took all microscopy pictures and 3D model. YTY, participated in developing and designing the RNA assay. RY, made all of the pathological paraffin slices. KKW, gene sequencing data analysis. QW, established CDX and PDX mice models. DDZ, participated in part of in vivo experiments. CJZ, collaborator from Henan Cancer hospital and provided ESCC tumor samples. KVL, manuscript revising and editing. MMG, took part in some cell culture experiments. WNN, protein MS analysis. KDL, co-corresponding author, project administration, management and coordination responsibility for the research activity planning and execution. ZGD, corresponding author, project supervision, oversight and leadership responsibility for the research activity planning and execution, including mentorship external to the core team.

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Correspondence to Kangdong Liu or Zigang Dong.

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The authors declare no competing interests.

Ethics approval and consent to participate

Tumor and adjacent ESCC tissues were obtained from ESCC cancer patients who underwent surgery at Henan Cancer Hospital. The experimental protocol was approved by the ethics committee of Zhengzhou University School of Medicine, Henan Cancer Hospital (No. 2017407). No patient received chemotherapy or radiotherapy prior to surgery. Animal experimental protocol was approved by the ethics committee of China-US (Henan) Hormel Cancer Institute (No. CUHCI2019003).

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Gao, Y., Jiang, M., Guo, F. et al. A novel lncRNA MTAR1 promotes cancer development through IGF2BPs mediated post-transcriptional regulation of c-MYC. Oncogene 41, 4736–4753 (2022). https://doi.org/10.1038/s41388-022-02464-x

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