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

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.

Data availability

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

References

  1. Milkereit P, Strauss D, Bassler J, Gadal O, Kuhn H, Schutz S, et al. A Noc complex specifically involved in the formation and nuclear export of ribosomal 40 S subunits. J Biol Chem. 2003;278:4072–81.

    CAS  PubMed  Google Scholar 

  2. Wild T, Horvath P, Wyler E, Widmann B, Badertscher L, Zemp I, et al. A protein inventory of human ribosome biogenesis reveals an essential function of exportin 5 in 60S subunit export. PLoS Biol. 2010;8:e1000522.

    PubMed  PubMed Central  Google Scholar 

  3. Warda AS, Freytag B, Haag S, Sloan KE, Gorlich D, Bohnsack MT. Effects of the Bowen-Conradi syndrome mutation in EMG1 on its nuclear import, stability and nucleolar recruitment. Hum Mol Genet. 2016;25:5353–64.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Zhu X, Zhang W, Guo J, Zhang X, Li L, Wang T, et al. Noc4L-mediated ribosome biogenesis controls activation of regulatory and conventional T cells. Cell Rep. 2019;27:1205–20 e4.

    CAS  PubMed  Google Scholar 

  5. Qin Y, Li H, Jia L, Yan J, Gao GF, Li X. Targeted disruption of Noc4l leads to preimplantation embryonic lethality in mice. Protein Cell. 2017;8:230–5.

    PubMed  Google Scholar 

  6. Yung BY, Busch H, Chan PK. Translocation of nucleolar phosphoprotein B23 (37 kDa/pI 5.1) induced by selective inhibitors of ribosome synthesis. Biochim Biophys Acta. 1985;826:167–73.

    CAS  PubMed  Google Scholar 

  7. Chan PK, Aldrich M, Busch H. Alterations in immunolocalization of the phosphoprotein B23 in HeLa cells during serum starvation. Exp Cell Res. 1985;161:101–10.

    CAS  PubMed  Google Scholar 

  8. Yang K, Wang M, Zhao Y, Sun X, Yang Y, Li X, et al. A redox mechanism underlying nucleolar stress sensing by nucleophosmin. Nat Commun. 2016;7:13599.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Lee S, Kim JY, Kim YJ, Seok KO, Kim JH, Chang YJ, et al. Nucleolar protein GLTSCR2 stabilizes p53 in response to ribosomal stresses. Cell Death Differ. 2012;19:1613–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Vaquero A, Scher M, Lee D, Erdjument-Bromage H, Tempst P, Reinberg D. Human SirT1 interacts with histone H1 and promotes formation of facultative heterochromatin. Mol Cell. 2004;16:93–105.

    CAS  PubMed  Google Scholar 

  11. Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001;107:149–59.

    CAS  PubMed  Google Scholar 

  12. Wong S, Weber JD. Deacetylation of the retinoblastoma tumour suppressor protein by SIRT1. Biochem J. 2007;407:451–60.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Bouras T, Fu M, Sauve AA, Wang F, Quong AA, Perkins ND, et al. SIRT1 deacetylation and repression of p300 involves lysine residues 1020/1024 within the cell cycle regulatory domain 1. J Biol Chem. 2005;280:10264–76.

    CAS  PubMed  Google Scholar 

  14. Wang C, Chen L, Hou X, Li Z, Kabra N, Ma Y, et al. Interactions between E2F1 and SirT1 regulate apoptotic response to DNA damage. Nat Cell Biol. 2006;8:1025–31.

    CAS  PubMed  Google Scholar 

  15. Brunet A, Sweeney LB, Sturgill JF, Chua KF, Greer PL, Lin Y, et al. Stress-dependent regulation of FOXO transcription factors by the SIRT1 deacetylase. Science 2004;303:2011–5.

    CAS  PubMed  Google Scholar 

  16. Zhang R, Chen HZ, Liu JJ, Jia YY, Zhang ZQ, Yang RF, et al. SIRT1 suppresses activator protein-1 transcriptional activity and cyclooxygenase-2 expression in macrophages. J Biol Chem. 2010;285:7097–110.

    CAS  PubMed  Google Scholar 

  17. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, et al. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell 2001;107:137–48.

    CAS  PubMed  Google Scholar 

  18. Deng CX. SIRT1, is it a tumor promoter or tumor suppressor? Int J Biol Sci. 2009;5:147–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lain S, Hollick JJ, Campbell J, Staples OD, Higgins M, Aoubala M, et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell. 2008;13:454–63.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Kabra N, Li Z, Chen L, Li B, Zhang X, Wang C, et al. SirT1 is an inhibitor of proliferation and tumor formation in colon cancer. J Biol Chem. 2009;284:18210–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Wu M, Wei W, Xiao X, Guo J, Xie X, Li L, et al. Expression of SIRT1 is associated with lymph node metastasis and poor prognosis in both operable triple-negative and non-triple-negative breast cancer. Med Oncol. 2012;29:3240–9.

    CAS  PubMed  Google Scholar 

  22. Chen HC, Jeng YM, Yuan RH, Hsu HC, Chen YL. SIRT1 promotes tumorigenesis and resistance to chemotherapy in hepatocellular carcinoma and its expression predicts poor prognosis. Ann Surg Oncol. 2012;19:2011–9.

    PubMed  Google Scholar 

  23. Cha EJ, Noh SJ, Kwon KS, Kim CY, Park BH, Park HS, et al. Expression of DBC1 and SIRT1 is associated with poor prognosis of gastric carcinoma. Clin Cancer Res. 2009;15:4453–9.

    CAS  PubMed  Google Scholar 

  24. Takemura M, Sato K, Nishio M, Akiyama T, Umekawa H, Yoshida S. Nucleolar protein B23.1 binds to retinoblastoma protein and synergistically stimulates DNA polymerase alpha activity. J Biochem. 1999;125:904–9.

    CAS  PubMed  Google Scholar 

  25. Kerr LE, Birse-Archbold JL, Short DM, McGregor AL, Heron I, Macdonald DC, et al. Nucleophosmin is a novel Bax chaperone that regulates apoptotic cell death. Oncogene. 2007;26:2554–62.

    CAS  PubMed  Google Scholar 

  26. Yao Z, Duan S, Hou D, Wang W, Wang G, Liu Y, et al. B23 acts as a nucleolar stress sensor and promotes cell survival through its dynamic interaction with hnRNPU and hnRNPA1. Oncogene 2010;29:1821–34.

    CAS  PubMed  Google Scholar 

  27. Wang H, Liu H, Chen K, Xiao J, He K, Zhang J, et al. SIRT1 promotes tumorigenesis of hepatocellular carcinoma through PI3K/PTEN/AKT signaling. Oncol Rep. 2012;28:311–8.

    PubMed  Google Scholar 

  28. Motta MC, Divecha N, Lemieux M, Kamel C, Chen D, Gu W, et al. Mammalian SIRT1 represses forkhead transcription factors. Cell 2004;116:551–63.

    CAS  PubMed  Google Scholar 

  29. Dai JM, Wang ZY, Sun DC, Lin RX, Wang SQ. SIRT1 interacts with p73 and suppresses p73-dependent transcriptional activity. J Cell Physiol. 2007;210:161–6.

    CAS  PubMed  Google Scholar 

  30. Wang L, Jia Y, Rogers H, Wu YP, Huang S, Noguchi CT. GATA-binding protein 4 (GATA-4) and T-cell acute leukemia 1 (TAL1) regulate myogenic differentiation and erythropoietin response via cross-talk with Sirtuin1 (Sirt1). J Biol Chem. 2012;287:30157–69.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305:390–2.

    CAS  PubMed  Google Scholar 

  32. Li K, Casta A, Wang R, Lozada E, Fan W, Kane S, et al. Regulation of WRN protein cellular localization and enzymatic activities by SIRT1-mediated deacetylation. J Biol Chem. 2008;283:7590–8.

    CAS  PubMed  Google Scholar 

  33. Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN, et al. Inhibition of SIRT1 reactivates silenced cancer genes without loss of promoter DNA hypermethylation. PLoS Genet. 2006;2:e40.

    PubMed  PubMed Central  Google Scholar 

  34. Liang XJ, Finkel T, Shen DW, Yin JJ, Aszalos A, Gottesman MM. SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism. Mol Cancer Res. 2008;6:1499–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell. 2008;14:312–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Cheng HL, Mostoslavsky R, Saito S, Manis JP, Gu Y, Patel P, et al. Developmental defects and p53 hyperacetylation in Sir2 homolog (SIRT1)-deficient mice. Proc Natl Acad Sci USA. 2003;100:10794–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Banks AS, Kon N, Knight C, Matsumoto M, Gutierrez-Juarez R, Rossetti L, et al. SirT1 gain of function increases energy efficiency and prevents diabetes in mice. Cell Metab. 2008;8:333–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Pfluger PT, Herranz D, Velasco-Miguel S, Serrano M, Tschop MH. Sirt1 protects against high-fat diet-induced metabolic damage. Proc Natl Acad Sci USA. 2008;105:9793–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Jang KY, Kim KS, Hwang SH, Kwon KS, Kim KR, Park HS, et al. Expression and prognostic significance of SIRT1 in ovarian epithelial tumours. Pathology 2009;41:366–71.

    CAS  PubMed  Google Scholar 

  40. Feng AN, Zhang LH, Fan XS, Huang Q, Ye Q, Wu HY, et al. Expression of SIRT1 in gastric cardiac cancer and its clinicopathologic significance. Int J Surg Pathol. 2011;19:743–50.

    CAS  PubMed  Google Scholar 

  41. Cao W, Jin H, Zhang L, Chen X, Qian H. Identification of miR-601 as a novel regulator in the development of pancreatic cancer. Biochem Biophys Res Commun. 2017;483:638–44.

    CAS  PubMed  Google Scholar 

  42. Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A, et al. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res. 2007;67:6612–8.

    CAS  PubMed  Google Scholar 

  43. Bradbury CA, Khanim FL, Hayden R, Bunce CM, White DA, Drayson MT, et al. Histone deacetylases in acute myeloid leukaemia show a distinctive pattern of expression that changes selectively in response to deacetylase inhibitors. Leukemia 2005;19:1751–9.

    CAS  PubMed  Google Scholar 

  44. Jang SH, Min KW, Paik SS, Jang KS. Loss of SIRT1 histone deacetylase expression associates with tumour progression in colorectal adenocarcinoma. J Clin Pathol. 2012;65:735–9.

    PubMed  Google Scholar 

  45. Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS ONE. 2008;3:e2020.

    PubMed  PubMed Central  Google Scholar 

  46. Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell. 2008;32:11–20.

    PubMed  PubMed Central  Google Scholar 

  47. Yeung F, Hoberg JE, Ramsey CS, Keller MD, Jones DR, Frye RA, et al. Modulation of NF-kappaB-dependent transcription and cell survival by the SIRT1 deacetylase. EMBO J. 2004;23:2369–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen WY, Wang DH, Yen RC, Luo J, Gu W, Baylin SB. Tumor suppressor HIC1 directly regulates SIRT1 to modulate p53-dependent DNA-damage responses. Cell 2005;123:437–48.

    CAS  PubMed  Google Scholar 

  49. Byles V, Chmilewski LK, Wang J, Zhu L, Forman LW, Faller DV, et al. Aberrant cytoplasm localization and protein stability of SIRT1 is regulated by PI3K/IGF-1R signaling in human cancer cells. Int J Biol Sci. 2010;6:599–612.

    PubMed  PubMed Central  Google Scholar 

  50. Honda R, Tanaka H, Yasuda H. Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 1997;420:25–7.

    CAS  PubMed  Google Scholar 

  51. Hafner A, Bulyk ML, Jambhekar A, Lahav G. The multiple mechanisms that regulate p53 activity and cell fate. Nat Rev Mol Cell Biol. 2019;20:199–210.

    CAS  PubMed  Google Scholar 

  52. Zhao J, Wozniak A, Adams A, Cox J, Vittal A, Voss J, et al. SIRT7 regulates hepatocellular carcinoma response to therapy by altering the p53-dependent cell death pathway. J Exp Clin Cancer Res. 2019;38:252.

    PubMed  PubMed Central  Google Scholar 

  53. Kim JK, Noh JH, Jung KH, Eun JW, Bae HJ, Kim MG, et al. Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b. Hepatology 2013;57:1055–67.

    CAS  PubMed  Google Scholar 

  54. Kandoth C, McLellan MD, Vandin F, Ye K, Niu B, Lu C, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013;502:333–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Giannakis M, Mu XJ, Shukla SA, Qian ZR, Cohen O, Nishihara R, et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 2016;17:1206.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 2012;487:330–7.

    Google Scholar 

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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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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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