Repression of YEATS2 induces cellular senescence in hepatocellular carcinoma and inhibits tumor growth

ABSTRACT

Hepatocellular carcinoma (HCC) stands as the third leading cause of cancer-related fatalities globally. In this study, we observed a significant increase in the expression level of the YEATS2 gene in HCC patients, and it is negatively correlated with the patients’ survival rate. While we have previously identified the association between YEATS2 and the survival of pancreatic cancer cells, the regulatory mechanisms and significance in HCC are still to be fully elucidated. Our study shows that knockdown (KD) of YEATS2 expression leads to DNA damage, which in turn results in an upregulation of γ-H2A.X expression and activation of the canonical senescence-related pathway p53/p21Cip1. Moreover, our transcriptomic analysis reveals that YEATS2 KD cells can enhance the expression of p21Cip1 via the c-Myc/miR-93-5p pathway, consequently fostering the senescence of HCC cells. The initiation of cellular senescence through dual-channel activation suggests that YEATS2 plays a pivotal regulatory role in the process of cell proliferation. Ultimately, our in vivo research utilizing a nude mouse tumor model revealed a notable decrease in both tumor volume and weight after the suppression of YEATS2 expression. This phenomenon is likely attributable to the attenuation of proliferative cell activity, coupled with a concurrent augmentation in the population of natural killer (NK) cells. In summary, our research results have supplemented the understanding of the regulatory mechanisms of HCC cell proliferation and indicated that targeting YEATS2 may potentially inhibit liver tumor growth.

KEYWORDS:

• YEATS2
• hepatocellular carcinoma
• senescence

Acknowledgements

We are grateful to the pzlink-yeats2 plasmid provided by Haitao Li at Tsinghua University.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Authors’ contributions

Feng Zhang, Qi Wu and Jinlin Ye research design; Qi Wu, Quan Zheng, Dandan Gao, Xinqing Jiang, Qiaocheng Zhai, Yabing Hu and Lei Yuan conducted experiments; Ming Liu, Lifeng Xu, Heng Xu, Qi Wu, Feng Zhang and Lei Yuan performed data analysis; Qi Wu, Quan Zheng, Jinlin Ye and Feng Zhang wrote or contributed to the writing of the manuscript.

Data availability statement

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

Ethical statement

This study was approved by the Ethics Committee of the Quzhou People’s Hospital (The Quzhou Affiliated Hospital of Wenzhou Medical University) (approval number: 2023018, Zhejiang, China). Each participant granted their consent by signing an informed consent form. The animal study approved by the Ethics Committee of Zhejiang Yingyang Pharmaceutical Research and Development Center, China (approval number: ZJEY-20230131-02).

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/15384101.2024.2342714

Additional information

Funding

This work was supported by Natural Science Foundation of China [82100893], Natural Science Foundation of Zhejiang Province [LGF22G010009, LZY24H160006], Chinese Medicine Science Foundation of Zhejiang Province [2021ZB328], Quzhou technology projects, China [2022K46, 2023K129, 2023K144].