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ZBTB28 inhibits breast cancer by activating IFNAR and dual blocking CD24 and CD47 to enhance macrophages phagocytosis

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Abstract

Breast cancer is the leading cause of cancer death in female. Until now, advanced breast cancer is still lack effective treatment strategies and reliable prognostic markers. In the present article, we introduced the physiologic and pathologic functions and regulation mechanisms of ZBTB28, a tumor suppressor gene, in breast cancer. ZBTB28 is frequently silenced in breast cancer due to promoter CpG methylation, and its expression is positively correlated with breast cancer patient survival. The antineoplastic effect of ZBTB28 in breast cancer was elucidated through a series of in vitro and in vivo measurements, including cell proliferation, apoptosis, cell cycle, epithelial mesenchymal transition (EMT), and growth of xenografts. Furthermore, ZBTB28 can directly regulate IFNAR to activate interferon-stimulated genes and potentiate macrophage activation. Ectopic ZBTB28 expression in breast cancer cells was sufficient to downregulate CD24 and CD47 to promote phagocytosis of macrophages, demonstrating that ZBTB28 was beneficial for the combination treatment of anti-CD24 and anti-CD47. Collectively, our results reveal a mode of action of ZBTB28 as a tumor suppressor gene and suggest that ZBTB28 is an important regulator of macrophage phagocytosis in breast cancer, holding promise for the development of novel therapy strategies for breast cancer patients.

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Fig. 1

available at UALCAN databases showing ZBTB28 expression and methylation in Luminal, HER2 positive and TNBC types of breast cancer tissues compared to normal mammary tissues. D The relationship between ZBTB28 expression and survival of patients with breast cancer were illustrated through Kaplan–Meier plots database. E The expression and CpG methylation level of ZBTB28 in normal breast cell line and several kinds of breast cancer cell lines. β-actin expression as control. F Western blot analysis confirmed the exogenous expression of ZBTB28 in normal breast cells and breast cancer cell lines, with GAPDH as a control. G ZBTB28 methylation in primary breast cancer tissues (n = 34) and normal breast tissues (n = 16) were measured by MSP (M methylated; U unmethylated)

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Availability of data and materials

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

Abbreviations

5-Aza:

5-Aza-2’-deoxycytidine

BrCa:

Breast cancer

ChIP:

Chromatin immunoprecipitation

EMT:

Epithelial–mesenchymal transition

IFNAR:

The type I IFN receptor

ISGs:

Interferon-stimulated genes

MSP:

Methylation-specific PCR

PMA:

12-Myristate 13-acetate

Siglec-10:

Sialic-acid-binding Ig-like lectin 10

SIRPα:

Signal regulatory protein alpha

TFBSs:

Transcription factor-binding sites

ZBTB28:

Zinc-finger and BTB/POZ (Poxvirus and Zinc-finger) domain-containing family protein 28

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Acknowledgements

This study was supported by National Natural Science Foundation of China (#81872380, #81572769, #82003135), Natural Science Foundation of Chongqing (2020ZYO13799), and Hong Kong-RGC (GRF# 14115019). The authors thank Prof. Qian Tao (the Chinese University of Hong Kong, Hong Kong, China) for generously providing primers and plasmids.

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Author notes

  1. Li Li, Yijia Gong, and Jun Tang have contributed equally to this work.

Authors and Affiliations

  1. Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Li Li, Yijia Gong, Jun Tang, Chun Yan, Weiyan Peng, Zhaobo Cheng, Renjie Yu, Qin Xiang, Chaoqun Deng, Junhao Mu, Jiuyi Xia, Xinrong Luo & Tingxiu Xiang

  2. Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Center for Cancer and Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China

    Lili Li

  3. Chongqing Key Laboratory of Translational Research for Cancer Metastasis and Individualized Treatment, Chongqing University Cancer Hospital, Chongqing, 400030, China

    Yongzhong Wu & Tingxiu Xiang

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  1. Li Li
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Contributions

LL and XT: conception and design. LL, GY, and TJ performed majority of experiments. PW, CZ, YR, DC, and LL performed experiments and analyzed data. XQ, MJ, YC, XJ, and WY collected samples. LL and GY drafted the manuscript. XT, LL, and GY reviewed data and manuscript. XT, LL, GY, and LX reviewed data and finalized the manuscript. All authors reviewed and approved the final version.

Corresponding author

Correspondence to Tingxiu Xiang.

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The study was authorized by the Institutional Ethics Committees of The First Affiliated Hospital of Chongqing Medical University and conformed to the principles of the Declaration of Helsinki.

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Li, L., Gong, Y., Tang, J. et al. ZBTB28 inhibits breast cancer by activating IFNAR and dual blocking CD24 and CD47 to enhance macrophages phagocytosis. Cell. Mol. Life Sci. 79, 83 (2022). https://doi.org/10.1007/s00018-021-04124-x

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