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A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy

Oncogene volume 37, pages 5829–5842 (2018)Cite this article

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Abstract

Circular RNAs are a large group of noncoding RNAs that are widely expressed in mammalian cells. Genome-wide analyses have revealed abundant and evolutionarily conserved circular RNAs across species, which suggest specific physiological roles of these species. Using a microarray approach, we detected increased expression of a circular RNA circ-Dnmt1 in eight breast cancer cell lines and in patients with breast carcinoma. Silencing circ-Dnmt1 inhibited cell proliferation and survival. Ectopic circ-Dnmt1 increased the proliferative and survival capacities of breast cancer cells by stimulating cellular autophagy. We found that circ-Dnmt1-mediated autophagy was essential in inhibiting cellular senescence and increasing tumor xenograft growth. We further found that ectopically expressed circ-Dnmt1 could interact with both p53 and AUF1, promoting the nuclear translocation of both proteins. Nuclear translocation of p53 induced cellular autophagy while AUF1 nuclear translocation reduced Dnmt1 mRNA instability, resulting in increased Dnmt1 translation. From here, functional Dnmt1 could then translocate into the nucleus, inhibiting p53 transcription. Computational algorithms revealed that both p53 and AUF1 could bind to different regions of circ-Dnmt1 RNA. Our results showed that the highly expressed circular RNA circ-Dnmt1 could bind to and regulate oncogenic proteins in breast cancer cells. Thus circ-Dnmt1 appears to be an oncogenic circular RNA with potential for further preclinical research.

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Acknowledgements

This work was supported by grants from Canadian Institutes of Health Research (PJT-153105), National Natural Science Foundation of Guangdong (2017A030310088), and Innovation and Entrepreneurship Leading Talent of Guangzhou Development Zone (2017-L181).

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    Authors and Affiliations

    1. Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada

      William W. Du, Weining Yang, Xiangmin Li, Faryal Mehwish Awan, Zhenguo Yang, Ling Fang, Juanjuan Lyu, Feiya Li, Nan Wu, Chao Zhang, Mouna Sdiri, Jun Dong, Jian Ma, Chunqi Gao, Steven Hibberd & Burton B Yang

    2. State Key Laboratory of Applied Microbiology Southern China, Guangdong Provincial Key Laboratory of Microbial Culture Collection and Application, Guangdong Institute of Microbiology, Guangzhou, 510070, People’s Republic of China

      Xiangmin Li & Yizhen Xie

    3. Atta-ur-Rahman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H-12, Islamabad, Pakistan

      Faryal Mehwish Awan

    4. China-Japan Union Hospital of Jilin University, Jilin, China

      Ling Fang & Chengyan He

    5. Department of Biology, York University, Toronto, Canada

      Chun Peng

    6. Department of Chemistry and Centre for Research on Biomolecular Interactions, York University, 4700 Keele Street, Toronto, Ontario, M3J 1P3, Canada

      Sergey N. Krylov

    7. Yuewei Edible Fungi Technology Co. Ltd., Guangzhou, China

      Yizhen Xie

    8. Key Lab in Healthy Science and Technology, Division of Life Science, Graduate School at Shenzhen, Tsinghua University, Shenzhen, 518055, People’s Republic of China

      Yaou Zhang

    9. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada

      Burton B Yang

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    These authors contributed equally: William W. Du, Weining Yang, Xiangmin Li, Faryal Mehwish Awan, Zhenguo Yang.

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    Du, W.W., Yang, W., Li, X. et al. A circular RNA circ-DNMT1 enhances breast cancer progression by activating autophagy. Oncogene 37, 5829–5842 (2018). https://doi.org/10.1038/s41388-018-0369-y

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