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KDM3B-ETF1 fusion gene downregulates LMO2 via the WNT/β-catenin signaling pathway, promoting metastasis of invasive ductal carcinoma

Cancer Gene Therapy volume 29, pages 215–224 (2022)Cite this article

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Abstract

Breast cancer is the most common malignancy for women, with invasive ductal carcinoma being the largest subtype of breast cancers, accounting for 75–80% of cases. However, the underlying mechanism of invasive ductal carcinoma remains unclear. In this study, we investigate the possible effects KDM3B-ETF1 fusion gene has on breast cancer cell metastasis, invasion and its downstream signaling mediators as revealed from RNA sequence data analysis. As predicted, KDM3B-ETF1 expression was increased in breast cancer tissues and cells. Overexpression of KDM3B-ETF1 in cancer cell lines promoted the growth and invasion of breast cancer cells, while KDM3B-ETF1 knockdown showed the opposite effects on malignant cell growth and invasion both in vivo and in vitro as evidenced by cell counting kit-8, Transwell assay and tumor xenograft in nude mice. On the contrary, LIM Domain Only 2 (LMO2) expression was significantly reduced in breast cancer tissues and cells. According to chromatin immunoprecipitation and Western blot analysis, KDM3B-ETF1 targets LMO2 and reduced the expression of LMO2, leading to an increase in WNT/β-catenin signaling pathway and thus promoting invasion. In conclusion, fusion gene KDM3B-ETF1 inhibits LMO2, activates the Wnt/β-catenin signaling pathway that leads to increased breast cancer cell invasion and metastasis, providing a novel insight into developing therapeutic strategies. These results provide novel insights into the molecular mechanism of invasive ductal carcinomas, which may lead to potential therapeutic targets.

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Fig. 1: KDM3B-ETF1 is expressed in breast cancer cell lines and tissues.
Fig. 2: KDM3B-ETF1 overexpression promotes breast cancer cell invasion.
Fig. 3: KDM3B-ETF1 mediates KDM3B expression and affects methyltransferase activity, regulating LMO2 expression.
Fig. 4: KDM3B-ETF1 activates the WNT/β-catenin signaling pathway by downregulating LMO2.
Fig. 5: KDM3B-ETF1 promotes breast cancer cell invasion by downregulating LMO2 and upregulating WNT/β-catenin signaling.
Fig. 6: KDM3B-ETF1 influences breast cancer cell growth in vivo.

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Acknowledgements

This study was supported by Key Science and Technology Projects of Department of science and technology in Henan Province (No. 161100311400).

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Author notes

  1. These authors contributed equally: Aixia Hu, Fan Hong

Authors and Affiliations

  1. Department of Pathology, Henan Provincial People’s Hospital, Zhengzhou, PR China

    Aixia Hu, Fan Hong, Daohong Li, Qi Xie, Lin Zhu & Hui He

  2. Henan University People’s Hospital, Zhengzhou, PR China

    Fan Hong

  3. Department of Pathology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China

    Kuisheng Chen

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  1. Aixia Hu
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  3. Daohong Li
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  6. Lin Zhu
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  7. Hui He
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Contributions

AH and KC designed the study. FH and LZ were involved in data collection. DL and QX performed the statistical analysis and preparation of figures. HH drafted the paper. All authors read and approved the final manuscript.

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Correspondence to Aixia Hu.

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The authors declare no competing interests.

Ethical approval

This study was approved by the ethics committee of Henan Provincial People’s Hospital in strict accordance with principles outlined in the Helsinki Declaration and the informed consent of all subjects was provided. Animal use and experimental procedures were performed with the approval of the Experimental Animal Ethics Committee of Henan Provincial People’s Hospital. All efforts were made to reduce the suffering of animals.

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Hu, A., Hong, F., Li, D. et al. KDM3B-ETF1 fusion gene downregulates LMO2 via the WNT/β-catenin signaling pathway, promoting metastasis of invasive ductal carcinoma. Cancer Gene Ther 29, 215–224 (2022). https://doi.org/10.1038/s41417-021-00301-z

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