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YPEL3 expression induces cellular senescence via the Hippo signaling pathway in human breast cancer cells

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Abstract

The Hippo pathway is a signaling pathway that controls organ size in animals by regulating cell proliferation and apoptosis. Yes-associated protein 1 (YAP1), an oncogene associated with the development and progression of breast cancer, is downregulated by the Hippo pathway and is associated with the development and progression of breast cancer. Yippee-like 3 (YPEL3) is a target gene of the tumor suppressor protein p53, and its activation has been shown to inhibit cell growth, induce cellular senescence, and suppress tumor cell metastasis. In this study, we found that YAP1 inhibits the expression of YPEL3 expression in breast cancer cells. Furthermore, a decrease in lamin B1, a marker protein of cellular senescence, coupled with the activation of senescence-associated β-galactosidase indicated that upregulating YPEL3 levels through YAP1 downregulation can induce cellular senescence. Additionally, elevated YPEL3 levels resulted in higher levels of oxygen consumption rate in mitochondria, thus promoting apoptosis. This suggests that YPEL3 plays a crucial role in regulating oxidative stress and cell apoptosis in breast cancer cells. Therefore, the interaction between YAP1 and YPEL3 represents a novel mechanism of cellular senescence mediated by the Hippo signaling pathway. Collectively, our findings suggest that the Hippo signaling pathway plays an important role in regulating cellular senescence, which could have implications for the development of new therapeutic strategies for diseases such as cancer.

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Data availability

The Kaplan–Meier plot data that supports this study are available on the Kaplan–Meier Plotter website (https://kmplot.com/analysis/). Further information about our study can be provided by the corresponding author upon reasonable request.

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Funding

This research was supported by the National Research Foundation of Korea (NRF) funded by the Korean government (MSIP) (Grant no. 2021R1A2C201239513, 2022R1A5A600076012) and the Chung-Ang University Graduate Research Scholarship in 2021. The funding agency had no role in the study design, data collection or analysis, the decision to publish, or the preparation of the manuscript.

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  1. Yeonju Kwon and Hyein Lee contributed equally to this study.

Authors and Affiliations

  1. College of Pharmacy and Center for Metareceptome Research, Chung-Ang University, 84 Heukseok-ro, Dongjak-gu, Seoul, 06974, Republic of Korea

    Yeonju Kwon, Hyein Lee, Hyemin Park, Boyoung Lee, Tae-Uk Kwon, Yeo-Jung Kwon & Young-Jin Chun

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  1. Yeonju Kwon
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Correspondence to Young-Jin Chun.

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Kwon, Y., Lee, H., Park, H. et al. YPEL3 expression induces cellular senescence via the Hippo signaling pathway in human breast cancer cells. Toxicol Res. 39, 711–719 (2023). https://doi.org/10.1007/s43188-023-00208-x

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