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FMR1/circCHAF1A/miR-211-5p/HOXC8 feedback loop regulates proliferation and tumorigenesis via MDM2-dependent p53 signaling in GSCs

Oncogene volume 40, pages 4094–4110 (2021)Cite this article

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Abstract

Glioma is the most common and fatal primary malignant brain tumor. Glioma stem cells (GSCs) may be an important factor in glioma cell proliferation, invasion, chemoradiotherapy tolerance, and recurrence. Therefore, discovering novel GSCs related circular RNAs (circRNAs) may finds out a prospective target for the treatment of glioma. A novel circRNA-CHAF1A (circCHAF1A) was first found in our study. CircCHAF1A was overexpressed in glioma and related to the low survival rate. Functionally, it was found that no matter in vitro or in vivo, circCHAF1A can facilitate the proliferation and tumorigenesis of TP53wt GSCs. Mechanistically, circCHAF1A upregulated transcription factor HOXC8 expression in GSCs through miR-211-5p sponging. Then, HOXC8 can transcriptionally upregulate MDM2 expression and inhibited the antitumor effect of p53. Furtherly, the RNA binding protein FMR1 can bind to and promoted the expression of circCHAF1A via maintaining its stability, while HOXC8 also transcribed the FMR1 expression to form a feedback loop, which may be involved in the malignant transformation of glioma. The novel feedback loop among FMR1, circCHAF1A, miR-211-5p, and HOXC8 in GSCs can facilitate the proliferation and tumorigenesis of glioma and GSCs. It also provided a helpful biomarker for diagnosis and prognostic evaluation of glioma and may be applied to molecular targeted therapy.

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Fig. 1: CircCHAF1A is upregulated in glioblastomas tissues and correlated with the progression and poor prognosis.
Fig. 2: CircCHAF1A regulates the proliferation of GSCs in vitro.
Fig. 3: HOXC8 is upregulated in glioblastomas tissues and correlated with the progression and poor prognosis.
Fig. 4: HOXC8 promotes the proliferation of GSCs in vitro via MDM2-dependent p53 inhibition.
Fig. 5: CircCHAF1A acts as a miRNA sponge of miR-211-5p and upregulates HOXC8 expression.
Fig. 6: CircCHAF1A promotes the proliferation of GSCs via HOXC8.
Fig. 7: FMR1 bound to and upregulate circCHAF1A expression in GSCs, while HOXC8 transcriptionally regulates U2AF2 expression.
Fig. 8: The U2AF2/ circCHAF1A /miR-211-5p/HOXC8 feedback loop promoted GSCs tumorigenesis in vivo.

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Acknowledgements

We thank Zhitao Jing at the Department of Neurosurgery, The First Affiliated Hospital of China Medical University for molecular experimental technical support. This work was supported by the National Natural Science Foundation of China (81900544), Key disciplines-B neurosurgery of Shanghai Tenth People’s Hospital (DS04! 02! 18014), and the Shanghai Sailing Program (No. 19YF1439000, No. 21YF1449900).

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Authors and Affiliations

  1. Department of Neurosurgery, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

    Yang Jiang, Tao Zeng & Liang Gao

  2. Department of Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Zhenlin Wang & Chenting Ying

  3. Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

    Jiangfeng Hu

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LG conceived and designed the study; YJ, ZLW, and CTY performed the experiments and collected the data; TZ, YJ, and JFH performed bioinformatics analysis and analyzed it. YJ, ZLW, and LG interpreted the results and wrote the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Liang Gao.

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Jiang, Y., Wang, Z., Ying, C. et al. FMR1/circCHAF1A/miR-211-5p/HOXC8 feedback loop regulates proliferation and tumorigenesis via MDM2-dependent p53 signaling in GSCs. Oncogene 40, 4094–4110 (2021). https://doi.org/10.1038/s41388-021-01833-2

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