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CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis


Increasing studies have indicated that circular RNAs (circRNAs) play pivotal roles in various cancers. Here, we aimed to explore the roles of circRNAs in breast cancer. We identified a novel circRNA circKDM4B (hsa_circ_0002926) by whole-transcriptome sequencing and validated this by Real-time quantitative polymerase chain reaction (RT-qPCR) and Sanger sequencing. It was significantly decreased in breast cancer tissues compared with adjacent non-tumor tissues. Furthermore, circKDM4B, which is mainly localized in the cytoplasm, was more resistant to actinomycin D or ribonuclease R than its linear transcript KDM4B. In addition, the overexpression of circKDM4B inhibited cell migration and invasion in vitro, while knockdown of circKDM4B induced the opposite effects. In vivo, circKDM4B suppressed tumor growth and metastasis. Additionally, circKDM4B inhibited migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. Mechanically, circKDM4B sponged miR-675 to upregulate the expression of NEDD4-like E3 ubiquitin protein ligase (NEDD4L), which catalyzes ubiquitination of PI3KCA, thereby inhibiting PI3K/AKT and VEGFA secretion. Collectively, these findings uncovered the tumor-suppressor role of circKDM4B in breast cancer, especially in angiogenesis and tumor metastasis, indicating that circKDM4B could be a potential therapeutic target for breast cancer progression.

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Fig. 1: Characterization of circKDM4B, which is significantly decreased in BC tissues.
Fig. 2: CircKDM4B inhibits cell migration and invasion in BC cells.
Fig. 3: CircKDM4B serves as a molecular sponge for miR-675 in BC cells.
Fig. 4: NEDD4L is a direct target of miR-675 and can be upregulated by circKDM4B.
Fig. 5: CircKDM4B negatively regulates PI3KCA by ubiquitination and inhibits PI3K/AKT signaling and VEGFA expression via miR-675/NEDD4L axis.
Fig. 6: CircKDM4B could be a promising target for BC treatment.


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We thank LetPub ( for its linguistic assistance during the preparation of this manuscript.


This study was supported by the National Natural Science Foundation of China (Grant nos. 81872362 and 82072665), the Taishan Scholars Program of Shandong Province (Grant no. ts201511096).

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X-YG and PG conceived the experiment and wrote the manuscript. X-YG performed the experiments and analysed the data. T-TL, W-J, H-TL, G-HZ, L-S, R-NZ, and XC helped with the experiments and analysis.

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Correspondence to Peng Gao.

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This study was approved by the Ethics Committee of Shandong University and conformed to the ethical standards of Helsinki Declaration. Informed consent was obtained from all patients included in this study.

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Guo, XY., Liu, TT., Zhu, WJ. et al. CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis. Oncogene 41, 1895–1906 (2022).

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