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ZNF133 is a potent suppressor in breast carcinogenesis through dampening L1CAM, a driver for tumor progression

Oncogene volume 42, pages 2166–2182 (2023)Cite this article

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Abstract

Due to the complexity and heterogeneity of breast cancer, the therapeutic effects of breast cancer treatment vary between subtypes. Breast cancer subtypes are classified based on the presence of molecular markers for estrogen or progesterone receptors and human epidermal growth factor 2. Thus, novel, comprehensive, and precise molecular indicators in breast carcinogenesis are urgently needed. Here, we report that ZNF133, a zinc-finger protein, is negatively associated with poor survival and advanced pathological staging of breast carcinomas. Moreover, ZNF133 is a transcription repressor physically associated with the KAP1 complex. It transcriptionally represses a cohort of genes, including L1CAM, that are critically involved in cell proliferation and motility. We also demonstrate that the ZNF133/KAP1 complex inhibits the proliferation and invasion of breast cancer cells in vitro and suppresses breast cancer growth and metastasis in vivo by dampening the transcription of L1CAM. Taken together, the findings of our study confirm the value of ZNF133 and L1CAM levels in the diagnosis and prognosis of breast cancer, contribute to a deeper understanding of the regulation mechanism of ZNF133 for the first time, and provide a new therapeutic strategy and precise intervention target for breast cancer.

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Fig. 1: Clinicopathological relevance of ZNF133 in breast carcinomas.
Fig. 2: Expression of ZNF133 is downregulated in breast cancer tissues.
Fig. 3: ZNF133 is a transcription repressor.
Fig. 4: Identification of ZNF133-associated proteins.
Fig. 5: Identification of transcriptional targets for ZNF133.
Fig. 6: Transcription repression of L1CAM by KAP1 complex.
Fig. 7: ZNF133/KAP1 complex suppresses the proliferation and invasion of breast cancer cells through inhibition of L1CAM in vitro.
Fig. 8: ZNF133 restrain the growth and metastasis of breast cancer in vivo.

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Data availability

ChIP-seq data for ZNF133 has been deposited in the Gene Expression Omnibus (GEO) with an accession number GSE226190. Data for Kaplan–Meier survival analysis in breast cancer patients are publicly available online at http://kmplot.com/analysis/index.php?p=background. Data for Gene expression-based Outcome for Breast cancer Online (GOBO) analysis are available from http://co.bmc.lu.se/gobo/gsa.pl. Data for Gene Expression Profiling Interactive Analysis (GEPIA) analysis are available from http://gepia.cancer-pku.cn/. Data for mRNA expression analysis in breast cancer patients are available in the Oncomine database at https://www.oncomine.org/. Access to publicly available cancer TCGA data is provided in the UALCAN web resource at http://ualcan.path.uab.edu/index.html. The open reading frame, conserved domains, and chromosomal location of ZNF133 were analyzed using the Uniprot (https://www.uniprot.org/) and NCBI (www.ncbi.nlm.nih.gov) databases. The theoretical molecular weight of ZNF133 was calculated using http://www.detaibio.com/sms2/protein_mw.html tools. The homologous alignment and phylogenetic analysis were performed using the MegAlign with Clustal V method.

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Funding

Funding

This work was supported by grants from the National Natural Science Foundation of China (81902811, 82002977, 82103387 and 82203471), and Tianjin Natural Science Foundation (Nos. 20JCZDJC00030 and 19JCZDJC65800).

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Author notes

  1. These authors contributed equally: Lifang Li, Xuefei Wang, Kai Hu.

Authors and Affiliations

  1. Department of Cancer Cell Biology, Tianjin’s Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, PR China

    Lifang Li, Xuefei Wang, Li Qiu, Hailong Wang, Runfen Cheng, Jialei Hua, Linyue Hai, Mengdie Wang, Miao Liu, Zian Song & Binghui Li

  2. Department of Pathology, School of Medicine, Nankai University, Tianjin, 300071, PR China

    Kai Hu

  3. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Hangzhou Normal University, Hangzhou, 311121, PR China

    Xinhua Liu

  4. Department of Clinical Laboratory, Tianjin’s Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, PR China

    Changsen Bai

  5. Public Laboratory, Tianjin’s Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, PR China

    Yanfen Cui

  6. Laboratory Animal Center, Tianjin’s Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, PR China

    Biyun Wang & Zhaosong Wang

  7. First Surgical Department of Breast Cancer, Tianjin’s Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, PR China

    Chunhua Xiao

  8. Beijing Institute of Hepatology, Beijing Youan Hospital, Capital Medical University, Beijing, 100069, PR China

    Binghui Li

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Contributions

LL, XW, and KH conceived and designed the study, performed experiments, and analyzed data; KH and YC performed animal experiments and pathologic analysis; XL analyzed the clinical datasets; LQ, BW, ZW, HW, JH, LH, MW, and ZS provided technical assistance. XL, CB, YC, RC, ML, and CX provided funding support and some ideas. LL drafted the paper; BL and LL discussed and finalized the paper. We thank Home for Researchers editorial team (www.home-for-researchers.com) for language editing service.

Corresponding authors

Correspondence to Lifang Li, Chunhua Xiao or Binghui Li.

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The authors declare no competing interests.

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Animal handling and procedures were approved by the Animal Ethical and Welfare Committee (AEWC) of Tianjin Medical University Cancer Institute and Hospital (NSFC-AE-2022199). The use of the TMAs complied with relevant regulations, and was approved by the Ethics Committee of Tianjin Medical University Cancer Institute and Hospital.

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Li, L., Wang, X., Hu, K. et al. ZNF133 is a potent suppressor in breast carcinogenesis through dampening L1CAM, a driver for tumor progression. Oncogene 42, 2166–2182 (2023). https://doi.org/10.1038/s41388-023-02731-5

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