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LACTB, a novel epigenetic silenced tumor suppressor, inhibits colorectal cancer progression by attenuating MDM2-mediated p53 ubiquitination and degradation

A Correction to this article was published on 06 May 2021

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Abstract

Colorectal cancer (CRC) is one of the most common aggressive malignancies. Like other solid tumors, inactivation of tumor suppressor genes and activation of oncogenes occur during CRC development and progression. Recently, a novel tumor suppressor, LACTB, was proposed to inhibit tumor progression, but the functional and clinical significance of this tumor suppressor in CRC remains unexplored. Herein, we found LACTB was significantly downregulated in CRC due to promoter methylation and histone deacetylation, which was associated with metastasis and advanced clinical stage. CRC patients with low LACTB expression had poorer overall survival and LACTB also determined to be an independent prognostic factor for poorer outcome. Ectopic expression of LACTB suppressed CRC cells proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) in vitro and inhibited CRC growth and metastasis in vivo, while knockout of LACTB by CRISPR/Cas9 gene editing technique resulted in an opposite phenotype. Interestingly, LACTB could exert antitumorigenic effect only in HCT116 and HCT8 cells harboring wild-type TP53, but not in HT29 and SW480 cells harboring mutant TP53 or HCT116 p53-/- cells. Mechanistic studies demonstrated that LACTB could directly bind to the C terminus of p53 to inhibit p53 degradation by preventing MDM2 from interacting with p53. Moreover, ablation of p53 attenuated the antitumorigenic effects of LACTB overexpression in CRC. Collectively, our findings successfully demonstrate for the first time that LACTB is a novel epigenetic silenced tumor suppressor through modulating the stability of p53, supporting the pursuit of LACTB as a potential therapeutic target for CRC.

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References

  1. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017;67:7–30.

    Article  Google Scholar 

  2. Markowitz SD, Bertagnolli MM. Molecular origins of cancer: molecular basis of colorectal cancer. N Engl J Med. 2009;361:2449–60.

    Article  CAS  Google Scholar 

  3. Peitsaro N, Polianskyte Z, Tuimala J, Porn-Ares I, Liobikas J, Speer O, et al. Evolution of a family of metazoan active-site-serine enzymes from penicillin-binding proteins: a novel facet of the bacterial legacy. BMC Evol Biol. 2008;8:26.

    Article  Google Scholar 

  4. Smith TS, Southan C, Ellington K, Campbell D, Tew DG, Debouck C. Identification, genomic organization, and mRNA expression of LACTB, encoding a serine beta-lactamase-like protein with an amino-terminal transmembrane domain. Genomics. 2001;78:12–4.

    Article  CAS  Google Scholar 

  5. Polianskyte Z, Peitsaro N, Dapkunas A, Liobikas J, Soliymani R, Lalowski M, et al. LACTB is a filament-forming protein localized in mitochondria. Proc Natl Acad Sci USA. 2009;106:18960–5.

    Article  CAS  Google Scholar 

  6. Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, et al. Global, in vivo, and site-specific phosphorylation dynamics in signaling networks. Cell. 2006;127:635–48.

    Article  CAS  Google Scholar 

  7. Willer CJ, Schmidt EM, Sengupta S, Peloso GM, Gustafsson S, Kanoni S, et al. Discovery and refinement of loci associated with lipid levels. Nat Genet. 2013;45:1274–83.

    Article  CAS  Google Scholar 

  8. Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature. 2010;466:707–13.

    Article  CAS  Google Scholar 

  9. Bains RK, Wells SE, Flavell DM, Fairhall KM, Strom M, Le Tissier P, et al. Visceral obesity without insulin resistance in late-onset obesity rats. Endocrinology. 2004;145:2666–79.

    Article  CAS  Google Scholar 

  10. Lu JB, Yao XX, Xiu JC, Hu YW. MicroRNA-125b-5p attenuates lipopolysaccharide-induced monocyte chemoattractant protein-1 production by targeting inhibiting LACTB in THP-1 macrophages. Arch Biochem Biophys. 2016;590:64–71.

    Article  CAS  Google Scholar 

  11. Keckesova Z, Donaher JL, De Cock J, Freinkman E, Lingrell S, Bachovchin DA, et al. LACTB is a tumour suppressor that modulates lipid metabolism and cell state. Nature. 2017;543:681–6.

    Article  CAS  Google Scholar 

  12. Li HT, Dong DY, Liu Q, Xu YQ, Chen L. Overexpression of LACTB, a mitochondrial protein, that inhibits proliferation and invasion in glioma cells. Oncol Res. 2017, https://doi.org/10.3727/096504017X15030178624579.

    Article  CAS  Google Scholar 

  13. Levine AJ, Oren M. The first 30 years ofp53: growing ever more complex. Nat Rev Cancer. 2009;9:749–58.

    Article  CAS  Google Scholar 

  14. Kim T, Veronese A, Pichiorri F, Lee TJ, Jeon YJ, Volinia S, et al. p53 regulates epithelial–mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J Exp Med. 2011;208:875–83.

    Article  CAS  Google Scholar 

  15. Chang CJ, Chao CH, Xia W, Yang JY, Xiong Y, Li CW, et al. p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs. Nat Cell Biol. 2011;13:317–23.

    Article  CAS  Google Scholar 

  16. Yuan XW, Wang DM, Hu Y, Tang YN, Shi WW, Guo XJ, et al. Hepatocyte nuclear factor 6 suppresses the migration and invasive growth of lung cancer cells through p53 and the inhibition of epithelial–mesenchymal transition. J Biol Chem. 2013;288:31206–16.

    Article  CAS  Google Scholar 

  17. Powell E, Piwnica-Worms D, Piwnica-Worms H. Contribution of p53 to metastasis. Cancer Discov. 2014;4:405–14.

    Article  CAS  Google Scholar 

  18. Ye J, Wei X, Shang Y, Pan Q, Yang M, Tian Y, et al. Core 3 mucin-type O-glycan restoration in colorectal cancer cells promotes MUC1/p53/miR-200c-dependent epithelial identity. Oncogene. 2017;36:6391–407.

    Article  CAS  Google Scholar 

  19. Haupt Y, Maya R, Kazaz A, Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296–9.

    Article  CAS  Google Scholar 

  20. Inoue T, Geyer RK, Howard D, Yu ZK, Maki CG. MDM2 can promote the ubiquitination, nuclear export, and degradation of p53 in the absence of direct binding. J Biol Chem. 2001;276:45255–60.

    Article  CAS  Google Scholar 

  21. Carter S, Bischof O, Dejean A, Vousden KH. C-terminal modifications regulate MDM2 dissociation and nuclear export of p53. Nat Cell Biol. 2007;9:428–35.

    Article  CAS  Google Scholar 

  22. Lang V, Pallara C, Zabala A, Lobato-Gil S, Lopitz-Otsoa F, Farras R, et al. Tetramerization-defects of p53 result in aberrant ubiquitylation and transcriptional activity. Mol Oncol. 2014;8:1026–42.

    Article  CAS  Google Scholar 

  23. Chen YC, Chang MY, Shiau AL, Yo YT, Wu CL. Mitochondrial ribosomal protein S36 delays cell cycle progression in association with p53 modification and p21(WAF1/CIP1) expression. J Cell Biochem. 2007;100:981–90.

    Article  CAS  Google Scholar 

  24. Russo A, Esposito D, Catillo M, Pietropaolo C, Crescenzi E, Russo G. Human rpL3 induces G(1)/S arrest or apoptosis by modulatingp21 (waf1/cip1) levels in a p53-independent manner. Cell Cycle. 2013;12:76–87.

    Article  CAS  Google Scholar 

  25. Hirano Y, Ronai Z. A new function for p53 ubiquitination. Cell. 2006;127:675–7.

    Article  CAS  Google Scholar 

  26. Joerger AC, Fersht AR. The p53 pathway: origins, inactivation in cancer, and emerging therapeutic approaches. Annu Rev Biochem. 2016;85:375–404.

    Article  CAS  Google Scholar 

  27. Komarov PG, Komarova EA, Kondratov RV, Christov-Tselkov K, Coon JS, Chernov MV, et al. A chemical inhibitor of p53 that protects mice from the side effects of cancer therapy. Science. 1999;285:1733–7.

    Article  CAS  Google Scholar 

  28. Mukhopadhyay S, Antalis TM, Nguyen KP, Hoofnagle MH, Sarkar R. Myeloid p53 regulates macrophage polarization and venous thrombus resolution by inflammatory vascular remodeling in mice. Blood. 2017;129:3245–55.

    Article  CAS  Google Scholar 

  29. Vassilev LT, Vu BT, Graves B, Carvajal D, Podlaski F, Filipovic Z, et al. In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004;303:844–8.

    Article  CAS  Google Scholar 

  30. Sarkar S, O’Connell MR, Okugawa Y, Lee BS, Toiyama Y, Kusunoki M, et al. FOXD3 regulates CSC marker, DCLK1-S, and invasive potential: prognostic implications in colon cancer. Mol Cancer Res. 2017;15:1678–91.

    Article  CAS  Google Scholar 

  31. Xia L, Huang W, Bellani M, Seidman MM, Wu K, Fan D, et al. CHD4 has oncogenic functions in initiating and maintaining epigenetic suppression of multiple tumor suppressor genes. Cancer Cell. 2017;31:653–.e7.

    Article  CAS  Google Scholar 

  32. Walerych D, Lisek K, Sommaggio R, Piazza S, Ciani Y, Dalla E, et al. Proteasome machinery is instrumental in a common gain-of-function program of the p53 missense mutants in cancer. Nat Cell Biol. 2016;18:897–909.

    Article  CAS  Google Scholar 

  33. Lessel D, Wu D, Trujillo C, Ramezani T, Lessel I, Alwasiyah MK, et al. Dysfunction of the MDM2/p53 axis is linked to premature aging. J Clin Invest. 2017;127:3598–608.

    Article  Google Scholar 

  34. Nomura K, Klejnot M, Kowalczyk D, Hock AK, Sibbet GJ, Vousden KH, et al. Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity. Nat Struct Mol Biol. 2017;24:578–87.

    Article  CAS  Google Scholar 

  35. Muller PA, Vousden KH. Mutant p53 in cancer: new functions and therapeutic opportunities. Cancer Cell. 2014;25:304–17.

    Article  CAS  Google Scholar 

  36. Strano S, Dell’Orso S, Di Agostino S, Fontemaggi G, Sacchi A, Blandino G. Mutant p53: an oncogenic transcription factor. Oncogene. 2007;26:2212–9.

    Article  CAS  Google Scholar 

  37. Wade M, Li YC, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer. 2013;13:83–96.

    Article  CAS  Google Scholar 

  38. Leslie PL, Zhang Y. MDM2 oligomers: antagonizers of the guardian of the genome. Oncogene. 2016;35:6157–65.

    Article  CAS  Google Scholar 

  39. Liu Q, Chen Z, Jiang G, Zhou Y, Yang X, Huang H, et al. Epigenetic down regulation of G protein-coupled estrogen receptor (GPER) functions as a tumor suppressor in colorectal cancer. Mol Cancer. 2017;16:87.

    Article  Google Scholar 

  40. Ma Y, Yang Y, Wang F, Moyer MP, Wei Q, Zhang P, et al. Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/beta-catenin signalling pathway via suppression of activator protein 2alpha. Gut. 2016;65:1494–504.

    Article  CAS  Google Scholar 

  41. Zeng K, Wang Z, Ohshima K, Liu Y, Zhang W, Wang L, et al. BRAF V600E mutation correlates with suppressive tumor immune microenvironment and reduced disease-free survival in Langerhans cell histiocytosis. Oncoimmunology. 2016;5:e1185582.

    Article  Google Scholar 

Download references

Acknowledgements

This project was supported by grants from the National Nature Science Foundation of China (No. 81472027, 81501820) to SKW and YQP; Innovation team of Jiangsu provincial health-strengthening engineering by science and education to SKW.

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Correspondence to Shukui Wang.

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Zeng, K., Chen, X., Hu, X. et al. LACTB, a novel epigenetic silenced tumor suppressor, inhibits colorectal cancer progression by attenuating MDM2-mediated p53 ubiquitination and degradation. Oncogene 37, 5534–5551 (2018). https://doi.org/10.1038/s41388-018-0352-7

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