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ZNRF2 as an oncogene is transcriptionally regulated by CREB1 in breast cancer models

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Abstract

E3 ubiquitin ligase Zinc and Ring Finger 2 (ZNRF2) has been demonstrated to be engaged in the development of multiple cancers. Nevertheless, the function of ZNRF2 in breast cancer (BC) still unclear. In this work, we firstly analyzed the differentially expressed genes in BC by bioinformatics and found that ZNRF2 was highly expressed in BC. Consistently, we further confirmed that ZNRF2 was upregulated in BC tissues compared with adjacent normal tissues, and this was positively correlated with the poor prognosis and the higher pathological grades of patients with BC. Functional assays performed on HCC1937 and MCF-7 cells indicated that silencing of ZNRF2 suppressed cell proliferation, as evidenced by the decrease in the expression of cyclin A, PCNA and cyclin D1. Flow cytometry and Hoechst staining showed that knockdown of ZNRF2 induced cell apoptosis, which was verified by the upregulation of apoptosis genes such as Bax, cleaved PARP and Bim. ZNRF2 knockdown also inhibited in vivo tumor growth. But, instead, ZNRF2-overexpressed BC cells exhibited obvious malignant phenotypes. Additionally, we observed that cAMP response element binding protein 1 (CREB1) directly bound to the promoter sequence of ZNRF2 and thus activating its transcription, suggesting that ZNRF2 is transcriptionally regulated by CREB1. Additionally, ZNRF2 knockdown could reverse the proliferation-promoting action of CREB1 on BC cells, Hence, this study demonstrated that ZNRF2 might serve as a prospective therapeutic target for BC.

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Funding

This research was supported by Dalian Municipal Central Hospital.

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Authors and Affiliations

  1. Department of Thyroid Surgery, Dalian Municipal Central Hospital, Dalian, Liaoning, China

    Jin-Tao Liu

  2. Graduate School, Dalian Medical University, Dalian, Liaoning, China

    Zhen-Xuan Sun, Rui Zhong, Yi-Dan Zhang, Teng Wang & Jian-Heng Bao

  3. Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China

    Zhen-Xuan Sun

  4. Graduate School, China Medical University, Shenyang, Liaoning, China

    Yu-Dong Hou

  5. Department of Breast Surgery, The First Hospital of China Medical University, No. 155, Nanjing North Street, Shenyang, Liaoning, China

    Lei Zhang & Bo Chen

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  1. Jin-Tao Liu
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Contributions

J-TL, LZ, and BC performed study concept and design; J-TL, Z-XS, RZ, Y-DZ and TW performed development of methodology, and data curation; J-TL, Z-XS, RZ, Y-DH, JHB provided acquisition, analysis and interpretation of data, and statistical analysis; J-TL, LZ and BC. were responsible for the writing and review of the manuscript. LZ and BC provided technical and material support. All authors read and approved the final paper.

Corresponding authors

Correspondence to Lei Zhang or Bo Chen.

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The authors report no conflict of interest.

Ethical approval

The human subject study was approved by the Ethics Committee of Dalian Municipal Central Hospital (License no. 2022–044-01). The animal experiments were undertaken in strict compliance with the Guide for the Care and Use of Laboratory Animals, and was approved by the Ethics Committee of Dalian Municipal Central Hospital (License no. 2022–044-02).

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Liu, JT., Sun, ZX., Zhong, R. et al. ZNRF2 as an oncogene is transcriptionally regulated by CREB1 in breast cancer models. Human Cell 36, 1501–1515 (2023). https://doi.org/10.1007/s13577-023-00913-7

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