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Targeting CircAURKA prevents colorectal cancer progression via enhancing CTNNB1 protein degradation

Oncogene volume 43, pages 3388–3401 (2024)Cite this article

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Abstract

Tumor progression of colorectal cancer (CRC) seriously affects patient prognosis. For CRC patients with advanced-stage disease, it is still necessary to continuously explore more effective targeted therapeutic drugs. Circular RNAs (circRNAs) are involved in the regulation of tumor biology. We screened circAURKA, which was significantly highly expressed in CRC by previous high-throughput RNA sequencing. In vitro experiments were performed to investigate the effect of the circRNA on the proliferation and metastasis of HCT116 and SW480 cells. In addition, we used the EdU assay, Transwell assay, nude mouse xenograft tumor model and nude mouse tail vein metastasis model to examine the effect of circAURKA on the proliferation and metastasis of CRC. Mechanistically, fluorescent in situ hybridization (FISH), RNA pull-down, RNA immunoprecipitation (RIP), protein coimmunoprecipitation (co-IP) experiments and animal models were performed to confirm the underlying mechanisms of circAURKA. CircAURKA was significantly highly expressed in CRC tissues and colorectal cells and mainly present in the cytoplasm. The circRNA promoted the proliferation and metastasis of CRC cells in vitro and in vivo. In terms of the molecular mechanism, circAURKA inhibited the degradation of the CTNNB1 protein by promoting the interaction between ACLY and the CTNNB1 protein, thereby promoting the proliferation and metastasis of CRC cells. In addition, circAURKA stability was regulated by m6A methylation modification. This study revealed that circAURKA promoted the proliferation and metastasis of CRC by inhibiting CTNNB1 protein degradation, providing a basis for the development of targeted drugs to control CRC progression.

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Fig. 1: Expression of circAURKA in CRC cells, tissues and serum.
Fig. 2: Structure identification and cell localization of circAURKA.
Fig. 3: CircAURKA promotes proliferation and metastasis of CRC.
Fig. 4: Transcriptome sequencing, RIP and pulldown mining of circAURKA downstream molecules.
Fig. 5: CircAURKA effect on ACLY and CTNNB1 proteins.
Fig. 6: CircAURKA promotes CRC proliferation and metastasis through CTNNB1.
Fig. 7: Effect of m6A modification on the stability of circAURKA.
Fig. 8

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Data availability

All the data used in the current study are available from the corresponding authors upon reasonable request.

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Funding

This study was supported by The National Natural Science Foundation of China (82173055), Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (ZYCXTD2023017), The Provincial and Ministry Co-constructed Key Projects of Henan Medical Science and Technology (SBGJ202102134), Henan Provincial Health and Health Commission Joint Construction Project (LHGJ20200158), and Henan Province Young and Middle-aged Health Science and Technology Innovation Leading Talent Project (YXKC2022016).

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Author notes

  1. These authors contributed equally: Zhenqiang Sun, Pengyuan Dang, Yaxin Guo, Senbo Liu.

Authors and Affiliations

  1. Department of Colorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Zhenqiang Sun, Pengyuan Dang, Senbo Liu, Shengyun Hu, Haifeng Sun, Yanxin Xu, Jinbo Liu & Junhong Hu

  2. Henan Institute of Interconnected Intelligent Health Management, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Zhenqiang Sun, Pengyuan Dang, Senbo Liu, Yanxin Xu & Chen Chen

  3. Department of Clinical Laboratory, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Yaxin Guo

  4. Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Wenkang Wang

  5. Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China

    Zhenyu Ji

  6. Department of Radiotherapy, Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan, China

    Yang Liu

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Contributions

ZS, YL, and JH provided direction and guidance throughout the preparation of this manuscript. PD, YG, SL, YX, HS, WW, and CC performed all experiments in this study. PD, YG, SL, and SH performed the data analysis and wrote the manuscript. JL and ZJ collected the related references and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Zhenqiang Sun, Yang Liu or Junhong Hu.

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The authors declare no competing interests.

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The authors declare that all methods were performed in accordance with all relevant guidelines and regulations. The human cancer tissues used in this study were approved by Ethnics Committee of The First Affiliated Hospital of Zhengzhou University (2019-KY-423). The Zhengzhou University Institutional Animal Care and Use Committee reviewed and approved all animal research protocols.

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Sun, Z., Dang, P., Guo, Y. et al. Targeting CircAURKA prevents colorectal cancer progression via enhancing CTNNB1 protein degradation. Oncogene 43, 3388–3401 (2024). https://doi.org/10.1038/s41388-024-03155-5

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