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Hypoxia-induced circADAMTS6 in a TDP43-dependent manner accelerates glioblastoma progression via ANXA2/ NF-κB pathway

Oncogene volume 42, pages 138–153 (2023)Cite this article

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Abstract

Circular RNAs (circRNAs) play important roles in the malignant progression of tumours. Herein, we identified an unreported circRNA (hsa-circ-0072688, also named circADAMTS6) that is specifically upregulated in the hypoxic microenvironment of glioblastoma and closely correlated with poor prognosis of gliblastoma patients. We found that circADAMTS6 promotes the malignant progression of glioblastoma by promoting cell proliferation and inhibiting apoptosis. Mechanistically, the hypoxic tumour microenvironment upregulates circADAMTS6 expression through transcription factor activator protein 1 (AP-1) and RNA-binding protein TAR DNA-binding protein 43 (TDP43). Moreover, circADAMTS6 accelerates glioblastoma progression by recruiting and stabilising annexin A2 (ANXA2) in a proteasomes-dependent manner. Furthermore, we found T-5224 (AP-1 inhibitor) treatment induces downregulation of circADAMTS6 and then inhibits tumour growth. In conclusion, our findings highlight the important role of the circADAMTS6/ANXA2 axis based on hypoxic microenvironment in glioblastoma progression, as well as its regulation in NF-κB pathway. Targeting circADAMTS6 is thus expected to become a novel therapeutic strategy for glioblastoma.

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Fig. 1: CircADAMTS6 expression is upregulated in GBM cell lines, GSCs and GBM tissue samples.
Fig. 2: CircADAMTS6 promotes GBM growth in vitro and in vivo.
Fig. 3: Hypoxia transcriptionally upregulates circADAMTS6 expression via the AP-1 complex.
Fig. 4: Hypoxia accelerates the cyclization of circADAMTS6 by promoting the binding of TDP43 to introns of ADAMTS6 pre-mRNA.
Fig. 5: CircADAMTS6 affects ANXA2 stability by preventing its ubiquitination.
Fig. 6: CircADAMTS6 positively regulates the NF-κB pathway via ANXA2.
Fig. 7: The AP-1 inhibitor T-5224 blocks the biogenesis of circADAMTS6 in GBM.

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Data availability

The datasets used and analysed during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

We are grateful to Dr. Frederick F Lang and Dr. Krishna P.L. Bhat for providing GSC cell lines used in our study; and CGGA, TCGA, GEO, Granvendeel and Rembrandt for public sequence data. This work was supported by grants from the National Natural Science Foundation of China (Nos. 82273195; 81874083; 82072776; 82273286; 82072775; 82203419;), Natural Science Foundation of Shandong Province of China (Nos. ZR2019BH057；ZR2020QH174; ZR2021LSW025), the Jinan Science and Technology Bureau of Shandong Province (2021GXRC029), Key Clinical Research Project of Clinical Research Center of Shandong University (2020SDUCRCA011) and Taishan Pandeng Scholar Program of Shandong Province (No. tspd20210322).

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  1. Department of Neurosurgery, Qilu Hospital, Cheeloo College of Medicine and Institute of Brain and Brain-Inspired Science, Shandong University, Jinan, Shandong, China

    Shulin Zhao, Boyan Li, Rongrong Zhao, Ziwen Pan, Shouji Zhang, Wei Qiu, Qindong Guo, Yanhua Qi, Zijie Gao, Yang Fan, Huizhi Wang, Jianye Xu, Shaobo Wang, Qingtong Wang, Jiawei Qiu, Lin Deng, Xing Guo, Ping Zhang, Hao Xue & Gang Li

  2. Shandong Key Laboratory of Brain Function Remodeling, Jinan, Shandong, China

    Shulin Zhao, Boyan Li, Rongrong Zhao, Ziwen Pan, Shouji Zhang, Wei Qiu, Qindong Guo, Yanhua Qi, Zijie Gao, Yang Fan, Hao Xu, Ming Li, Jian Zhang, Huizhi Wang, Jianye Xu, Shaobo Wang, Qingtong Wang, Jiawei Qiu, Lin Deng, Xing Guo, Ping Zhang, Hao Xue & Gang Li

  3. Department of Neurosurgery, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong, China

    Hao Xu

  4. Department of Neurosurgery, Taian Central Hospital, Taian, Shandong, China

    Ming Li

  5. Department of Neurosurgery, Dezhou People’s Hospital, Dezhou, China

    Jian Zhang

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Contributions

GL, HX and SZ conceived and devised the study; BL, RZ, ZP, SZ, WQ, QG, YQ, ZG, YF, HX, ML and JZ performed the experiments; HW, XJ, SW and QW performed bioinformatics and statistical analysis; JQ and LD analysed the data. XG and PZ supervised the research. SZ, BL and RZ wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hao Xue or Gang Li.

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Zhao, S., Li, B., Zhao, R. et al. Hypoxia-induced circADAMTS6 in a TDP43-dependent manner accelerates glioblastoma progression via ANXA2/ NF-κB pathway. Oncogene 42, 138–153 (2023). https://doi.org/10.1038/s41388-022-02542-0

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