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Nucleolar protein NOC4L inhibits tumorigenesis and progression by attenuating SIRT1-mediated p53 deacetylation

Oncogene volume 41, pages 4474–4484 (2022)Cite this article

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Abstract

SIRT1 is an NAD+-dependent deacetylase and plays an important role in the deacetylation of both histone and non-histone proteins. Many studies revealed that SIRT1 is upregulated in a variety of tumors and tightly associated with tumorigenesis and cancer progression, but the detailed underlying mechanism of the biological processes remains unclarified. In the present study, we found a nucleolar protein NOC4L, human ortholog of yeast Noc4p, which is essential for the nuclear export of the ribosomal 40S subunit and could bind to SIRT1 to inhibit SIRT1 mediated deacetylation of p53. NOC4L interacts with SIRT1 in variety of cells under nucleolar stress and directly interacts with SIRT1 in vitro. Furthermore, we determined the C-terminal of NOC4L and the catalytic domain of SIRT1 were required for their interaction. Overexpression of NOC4L did not change the protein levels of SIRT1 or p53, but increased the acetylation of p53 and promoted cell apoptosis. Additionally, NOC4L inhibited tumor cell proliferation in a p53-dependent manner and restrained tumor growth in a nude mice xenograft model. Clinically, colorectal cancer patients with the high expression of NOC4L had a better prognosis as TP53 was normally expressed, but no significant difference was observed in survival with mutant TP53. Taken together, our results identified a novel SIRT1 regulatory protein and broaden our understanding of the molecular mechanism of how nucleolar protein NOC4L regulates p53 under nucleolar stress. This research provides an insight into tumorigenesis and cell self-protection in the early stage of DNA damage.

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Fig. 1: NOC4L interacts with SIRT1 under nucleolar stress.
Fig. 2: The C-terminal of NOC4L and the catalytic domain of SIRT1 are required for their interaction.
Fig. 3: NOC4L promoted p53 acetylation by inhibiting SIRT1 deacetylase activity.
Fig. 4: NOC4L promotes cell apoptosis and inhibits cell growth in a p53 depended way.
Fig. 5: NOC4L was upregulated and shuttled to nucleoplasm and cytoplasm under cell stress.
Fig. 6: Overexpression of NOC4L inhibited tumor growth in nude mice transplantation.

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Data availability

The survival data of Fig. 6E were obtained from TCGA COAD dataset (http://tcga-data.nci.nih.gov/tcga/).

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Acknowledgements

This study was supported by grants from National Natural Science Foundation of China (31970802); National Natural Science Foundation of China (82171854); Beijing Municipal Natural Science Foundation (7202099); Open Project of the State Key Laboratory of Agrobiotechnology (2022SKLAB6-05); Science & Technology Innovation Program for National Defense (19-163-15-ZD-009-001-03); Ji Nan Science & Technology Bureau (2021GXRC060); Medical University of Bialystok, Poland (SUB/1/DN/21/002/1104). We are grateful to Prof. Xiaojuan Du and Prof. Jianyuan Luo for advising this research. We thank Yun Liu for flow cytometry assistance. We thank Xin Ren for the revision of the manuscript language.

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  1. These authors contributed equally: Xiaomeng Jia, Huijiao Liu.

Authors and Affiliations

  1. State Key Laboratory of the Agro-Biotechnology, College of Biological Science, China Agricultural University, 100193, Beijing, China

    Xiaomeng Jia, Huijiao Liu, Xinmin Ren, Peng Li, Runjie Song & Xiangdong Li

  2. College of Horticultural Science, China Agricultural University, 100193, Beijing, China

    Huijiao Liu & Yangdong Guo

  3. Department of Nutrition and Human Health, China Agricultural University, Beijing, China

    Huijiao Liu & Xiangdong Li

  4. Department of General Surgery, Chinese PLA General Hospital, Beijing, China

    Xiru Li

  5. Department of Reproduction and Gynecological Endocrinology, Medical University of Bialystok, Bialystok, Poland

    Xiangdong Li

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HL, XJ, YG, XL and XL conceived and designed the study and contributed to the writing of the manuscript. HL, XJ, XR and PL performed the analysis procedures. HL and XJ analyzed the results. XL contributed to analysis data. All authors reviewed the manuscript.

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Correspondence to Xiangdong Li.

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Jia, X., Liu, H., Ren, X. et al. Nucleolar protein NOC4L inhibits tumorigenesis and progression by attenuating SIRT1-mediated p53 deacetylation. Oncogene 41, 4474–4484 (2022). https://doi.org/10.1038/s41388-022-02447-y

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