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The interaction between S100A2 and KPNA2 mediates NFYA nuclear import and is a novel therapeutic target for colorectal cancer metastasis

Oncogene volume 41, pages 657–670 (2022)Cite this article

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Abstract

Nucleocytoplasmic transport of proteins is disrupted and dysregulated in cancer cells. Nuclear pore complexes and cargo proteins are two main transportation regulators. However, the mechanism regulating nucleocytoplasmic transport in cancer remains elusive. Here, we identified a S100A2/KPNA2 cotransport complex that transports the tumor-associated transcription factor NFYA in colorectal cancer (CRC). Through the S100A2/KNPA2 complex, depending on its interaction with S100A2, NFYA is transported to the nucleus and inhibits the transcriptional activity of E-cadherin, which in turn promotes CRC metastasis. Targeting the S100A2/KPNA2 binding sites with the specific inhibitor delanzomib is a potential therapeutic approach for CRC.

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Fig. 1: High expression of S100A2 is correlated with poor prognosis in CRC.
Fig. 2: Biological function of S100A2 in CRC metastasis.
Fig. 3: S100A2 and KPNA2 bind to each other and regulate the cellular localization of S100A2.
Fig. 4: S100A2 regulates the translocation of NFYA through binding to KPNA2.
Fig. 5: Binding model of the NFYA/S100A2/KPNA2 complex.
Fig. 6: S100A2 induces metastasis by regulating NFYA-mediated downregulation of E-cadherin.
Fig. 7: Delanzomib blocks the interaction between KPNA2 and S100A2 and inhibits CRC metastasis.
Fig. 8: Model of the S100A2/KPNA2 complex in regulation of NFYA nuclear import.

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Data availability

The accession number for RNA sequencing data is PRJNA778318 and other data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Additional data related to this paper may be requested from the authors.

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Acknowledgements

We thank Qiong Huang and Yangwei Li from the core facility platform of Zhejiang University School of Medicine for their technical support. We thank Professor Jimin Shao lab for providing vectors of pGL3-basic, pRL-TK, pGEX-GST, and pET-28a-His and Run Run Shaw Hospital, Zhejiang University for providing colorectal carcinoma samples and serum from patients. We thank Shenghui Hong and Ping Liu in the Laboratory Animal Center of Zhejiang University for their technical assistance on breeding and management of mice.

Funding

This work is supported by the National Natural Science Foundation of China (81871937, 82001586, 91859204, 82072629, 82072811) and CAMS Innovation Fund for Medical Sciences (CIFMS, 2019-I2M-5-044).

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  1. These authors contributed equally: Fengyan Han, Lei Zhang.

Authors and Affiliations

  1. Department of Pathology and Women’s Hospital, Zhejiang University School of Medicine, Research Unit of Intelligence Classification of Tumor Pathology and Precision Therapy, Chinese Academy of Medical Sciences (2019RU042), Hangzhou, 310058, Zhejiang, China

    Fengyan Han, Shaoxia Liao, Lili Qian, Feijun Hou & Honghe Zhang

  2. Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, 310058, Zhejiang, China

    Lei Zhang, Jingwen Gong, Maode Lai & Honghe Zhang

  3. Cancer Center, Zhejiang University, Hangzhou, 310058, Zhejiang, China

    Lei Zhang, Jingwen Gong, Maode Lai & Honghe Zhang

  4. Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, China

    Lei Zhang & Maode Lai

  5. Laboratory of Molecular Design and Drug Discovery, School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing, 211198, China

    Yanmin Zhang

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Contributions

Conceptualization: HZ and ML; methodology: F Han, LZ, SL, and LQ; investigation: F Han, LZ, SL, F Hou, and JG; resources: F Han, LZ, LQ, and F Hou; writing—original draft: F Han and LZ; writing—review and editing: HZ and ML; supervision: HZ and ML; funding acquisition: HZ and ML.

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Correspondence to Maode Lai or Honghe Zhang.

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Han, F., Zhang, L., Liao, S. et al. The interaction between S100A2 and KPNA2 mediates NFYA nuclear import and is a novel therapeutic target for colorectal cancer metastasis. Oncogene 41, 657–670 (2022). https://doi.org/10.1038/s41388-021-02116-6

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