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NAD+ supplementation limits triple-negative breast cancer metastasis via SIRT1-P66Shc signaling

Oncogene volume 42, pages 808–824 (2023)Cite this article

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Abstract

NAD+ levels decline with age and in certain disease conditions. NAD+ precursors have been shown to stimulate NAD+ biosynthesis and ameliorate various age-associated diseases in mouse models. However, NAD+ metabolism is complicated in cancer and its role in triple-negative breast cancer (TNBC) remains elusive. Here, we show that NAD+ supplement suppresses tumor metastasis in a TNBC orthotopic patient-derived xenograft (PDX) model. Sirtuin1 lysine deacetylase (SIRT1) is required for the effects since SIRT1 knockdown blocks NAD+-suppressed tumor metastasis. Overexpression of SIRT1 effectively impairs the metastatic potential of TNBC. Importantly, the interaction between SIRT1 and p66Shc causes the deacetylation and functional inactivation of p66Shc, which inhibits epithelial-mesenchymal transition (EMT). Overall, we demonstrate that NAD+ supplementation executes its anti-tumor function via activating the SIRT1-p66Shc axis, which highlights the preventive and therapeutic potential of SIRT1 activators as effective interventions for TNBC.

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Fig. 1: NAD+ supplementation suppresses TNBC progression.
Fig. 2: The expression of SIRT1 in clinical samples and TNBC cells.
Fig. 3: SIRT1 suppresses the invasive ability of TNBC cells and tumor metastasis.
Fig. 4: Targeting SIRT1 blocks NAD+-inhibited tumor metastasis.
Fig. 5: SIRT1 interacts with P66Shc and mediates its acetylation and phosphorylation.
Fig. 6: NAD+ metabolism regulates the acetylation and phosphorylation of P66Shc via SIRT1.
Fig. 7: NAD+ supplementation suppresses tumor metastasis by regulating the SIRT1/P66Shc signaling and EMT process.
Fig. 8: A proposed model depicting that NAD+ supplementation induces SIRT1 activation in TNBC.

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Data availability

The RNA sequence data in the present study have been deposited in the NCBI Gene Expression Omnibus (GEO) public database with the accession number GSE220683. All data are available from the authors upon reasonable request.

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Acknowledgements

We thank all the staff members of Luo laboratory for their technical support and critical suggestions. This work was supported by the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No. 20181821569) and the Self-Topic Fund of Tsinghua University (No. 20191080585).

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Authors and Affiliations

  1. Cancer Biology Laboratory, School of Life Sciences, Tsinghua University, 100084, Beijing, China

    Yi Jiang, Zongrui Luo, Yuanchao Gong, Yan Fu & Yongzhang Luo

  2. The National Engineering Research Center for Protein Technology, Tsinghua University, 100084, Beijing, China

    Yi Jiang, Zongrui Luo, Yuanchao Gong, Yan Fu & Yongzhang Luo

  3. Beijing Key Laboratory for Protein Therapeutics, Tsinghua University, 100084, Beijing, China

    Yi Jiang, Zongrui Luo, Yuanchao Gong, Yan Fu & Yongzhang Luo

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Conceptualization: YJ; Methodology: YJ and YG; Investigation: YJ and ZL; Writing—original draft: YJ; Writing—review and editing: YJ, ZL, YF and YL; Supervision: YL and YF; Funding acquisition: YL and YF.

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Correspondence to Yan Fu or Yongzhang Luo.

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Jiang, Y., Luo, Z., Gong, Y. et al. NAD+ supplementation limits triple-negative breast cancer metastasis via SIRT1-P66Shc signaling. Oncogene 42, 808–824 (2023). https://doi.org/10.1038/s41388-023-02592-y

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