Abstract
During tumourigenesis, p53 functions as 'the guardian of the genome' because p53-dependent apoptosis strongly regulates the fate of cancer cells. Therefore, p53 regulation must be sensitive and accurate. p53 activity is regulated through its ubiquitination and deubiquitination. However, the role of microRNA in ubiquitin-mediated p53 degradation has not been previously studied. Our previous studies indicated that miR-100 is required for apoptosis. In the current study, the mechanism of p53 protein ubiquitination mediated by miR-100 was characterized. An analysis of primary tumour samples from gastric cancer patients showed a significant correlation between miR-100 upregulation and primary human gastric tumourigenesis and progression. The in vivo and in vitro data indicated that miR-100 antagonism specifically induced the apoptosis of poorly differentiated gastric cancer cells but not non-cancerous gastric cells, indicating that miR-100 has a crucial role in regulating the progression of gastric tumours. In the regulation of p53-dependent apoptosis, miR-100 antagonism inhibited ubiquitin-mediated p53 protein degradation by activating RNF144B, an E3 ubiquitination ligase. Consequently, the miR-100-RNF144B-pirh2-p53-dependent pathway was initiated. Our findings highlight a novel mechanism of ubiquitin-mediated p53 protein degradation in apoptosis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Taylor RC, Cullen SP, Martin SJ . Apoptosis: controlled demolition at the cellular level. Nat Rev Mol Cell Bio 2008; 9: 231–241.
Medina-Ramirez CM, Goswami S, Smirnova T, Bamira D, Benson B, Ferrick N et al. Apoptosis inhibitor ARC promotes breast tumorigenesis, metastasis, and chemoresistance. Cancer Res 2011; 71: 7705–7715.
Zuckerman V, Wolyniec K, Sionov RV, Haupt S, Haupt Y . Tumour suppression by p53: the importance of apoptosis and cellular senescence. J Pathol 2009; 219: 3–15.
Deng Y, Chan SS, Chang S . Telomere dysfunction and tumour suppression: the senescence connection. Nat Rev Cancer 2008; 8: 450–458.
Mercer J, Mahmoudi M, Bennett M . DNA damage, p53, apoptosis and vascular disease. Mutat Res 2007; 621: 75–86.
Donehower LA, Lozano G . 20 years studying p53 functions in genetically engineered mice. Nat Rev Cancer 2009; 9: 831–841.
Feki A, Irminger-Finger I . Mutational spectrum of p53 mutations in primary breast and ovarian tumors. Crit Rev Oncol Hematol 2004; 52: 103–116.
Le MT, Teh C, Shyh-Chang N, Xie H, Zhou B, Korzh V et al. MicroRNA-125b is a novel negative regulator of p53. Gene Dev 2009; 23: 862–876.
Wang X . p53 regulation. Cell Cycle 2011; 10: 4225–4229.
Ravid T, Hochstrasser M . Diversity of degradation signals in the ubiquitin–proteasome system. Nat Rev Mol Cell Bio 2008; 9: 679–689.
Shang F, Taylor A . Ubiquitin–proteasome pathway and cellular responses to oxidative stress. Free Radical Bio Med 2011; 51: 5–16.
Adams J . The proteasome: structure, function, and role in the cell. Cancer Treat Rev 2003; 29: 3–9.
Bernassola F, Karin M, Ciechanover A, Melino G . The HECT family of E3 ubiquitin ligases: multiple players in cancer development. Cancer Cell 2008; 14: 10–21.
Motegi A, Murakawa Y, Takeda S . The vital link between the ubiquitin–proteasome pathway and DNA repair: Impact on cancer therapy. Cancer Lett 2009; 283: 1–9.
Allende-Vega N, Saville MK . Targeting the ubiquitin–proteasome system to activate wild-type p53 for cancer therapy. Semin Cancer Biol 2010; 20: 29–39.
Leng RP, Lin Y, Ma W, Wu H, Lemmers B, Chung S et al. Pirh2, a p53-induced ubiquitin-protein ligase, promotes p53 degradation. Cell 2003; 112: 779–791.
Laine A, Ronai ZE . Regulation of p53 localization and transcription by the HECT domain E3 ligase WWP1. Oncogene 2006; 26: 1477–1483.
Liu Z, Miao D, Xia Q, Hermo L, Wing SS . Regulated expression of the ubiquitin protein ligase, E3Histone/LASU1/Mule/ARF‐BP1/HUWE1, during spermatogenesis. Dev Dyn 2007; 236: 2889–2898.
Dornan D, Wertz I, Shimizu H, Arnott D, Frantz GD, Dowd P et al. The ubiquitin ligase COP1 is a critical negative regulator of p53. Nature 2004; 429: 86–92.
Tsvetkov P, Adamovich Y, Elliott E, Shaul Y . E3 ligase STUB1/CHIP regulates NAD (P) H: quinone oxidoreductase 1 (NQO1) accumulation in aged brain, a process impaired in certain Alzheimer disease patients. J Biol Chem 2011; 286: 8839–8845.
Ambros V . The functions of animal microRNAs. Nature 2004; 431: 350–355.
Bartel DP, Chen C-Z . Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 2004; 5: 396–400.
Esteller M . Non-coding RNAs in human disease. Nat Rev Genet 2011; 12: 861–874.
Lewis BP, Burge CB, Bartel DP . Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 2005; 120: 15–20.
Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA 2004; 101: 2999–3004.
Calin GA, Croce CM . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–866.
Yang G, Yang L, Zhao Z, Wang J, Zhang X . Signature miRNAs involved in the innate immunity of invertebrates. PLoS One 2012; 7: e39015.
Gong Y, He T, Yang L, Yang G, Chen Y, Zhang X . The role of miR-100 in regulating apoptosis of breast cancer cells. Sci Rep 2015; 5: e11650.
Pietsch EC, Sykes SM, McMahon SB, Murphy ME . The p53 family and programmed cell death. Oncogene 2008; 27: 6507–6521.
Barboza JA, Iwakuma T, Terzian T, El-Naggar AK, Lozano G . Mdm2 and Mdm4 loss regulates distinct p53 activities. Mol Cancer Res 2008; 6: 947–954.
Isaacson MK, Ploegh HL . Ubiquitination, ubiquitin-like modifiers, and deubiquitination in viral infection. Cell Host Microbe 2009; 5: 559–570.
Chen D, Zhang J, Li M, Rayburn ER, Wang H, Zhang R . RYBP stabilizes p53 by modulating MDM2. EMBO Rep 2009; 10: 166–172.
Christodoulou F, Raible F, Tomer R, Simakov O, Trachana K, Klaus S et al. Ancient animal microRNAs and the evolution of tissue identity. Nature 2010; 463: 1084–1088.
Wienholds E, Kloosterman WP, Miska E, Alvarez-Saavedra E, Berezikov E, de Bruijn E et al. MicroRNA expression in zebrafish embryonic development. Science 2005; 309: 310–311.
Shi W, Alajez NM, Bastianutto C, Hui AB, Mocanu JD, Ito E et al. Significance of Plk1 regulation by miR‐100 in human nasopharyngeal cancer. Int J Cancer 2010; 126: 2036–2048.
Wong T-S, Liu X-B, BY-H Wong, RW-M Ng, AP-W Yuen, Wei WI . Mature miR-184 as potential oncogenic microRNA of squamous cell carcinoma of tongue. Clin Cancer Res 2008; 14: 2588–2592.
Nam EJ, Yoon H, Kim SW, Kim H, Kim YT, Kim JH et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin Cancer Res 2008; 14: 2690–2695.
Cairo S, Wang Y, de Reyniès A, Duroure K, Dahan J, Redon M-J et al. Stem cell-like micro-RNA signature driven by Myc in aggressive liver cancer. Proc Natl Acad Sci USA 2010; 107: 20471–20476.
Henson BJ, Bhattacharjee S, O'Dee DM, Feingold E, Gollin SM . Decreased expression of miR‐125b and miR‐100 in oral cancer cells contributes to malignancy. Gene Chromosome Cancer 2009; 48: 569–582.
Liu W, Gong Y-H, Chao T-F, Peng X-Z, Yuan J-G, Ma Z-Y et al. Identification of differentially expressed microRNAs by microarray: a possible role for microRNAs gene in medulloblastomas. Chinese Med J 2009; 122: 2405–2411.
Leite KR, Sousa-Canavez JM, Reis ST, Tomiyama AH, Camara-Lopes LH, Sañudo A et al. Change in expression of miR-let7c, miR-100, and miR-218 from high grade localized prostate cancer to metastasis. Urol Oncol 2011; 29: 265–269.
Lee EJ, Gusev Y, Jiang J, Nuovo GJ, Lerner MR, Frankel WL et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int J Cancer 2007; 120: 1046–1054.
Conforti F, Yang AL, Piro MC, Mellone M, Terrinoni A, Candi E et al. PIR2/Rnf144B regulates epithelial homeostasis by mediating degradation of p21WAF1 and p63. Oncogene 2012; 32: 4758–4765.
Benard G, Neutzner A, Peng G, Wang C, Livak F, Youle RJ et al. IBRDC2, an IBR‐type E3 ubiquitin ligase, is a regulatory factor for Bax and apoptosis activation. EMBO J 2010; 29: 1458–1471.
Acknowledgements
This work was supported by the National Natural Science Foundation of China (41276152, 31430089) and the National Program on the Key Basic Research Project (2015CB755903).
Author contributions
GY, YG, QZW and LPW performed the experiments. XBZ, GY and YG designed the experiments and analysed the data. YG and XBZ wrote the manuscript. All authors read and approved the contents of the manuscript and its publication.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflicts of interest.
Rights and permissions
About this article
Cite this article
Yang, G., Gong, Y., Wang, Q. et al. miR-100 antagonism triggers apoptosis by inhibiting ubiquitination-mediated p53 degradation. Oncogene 36, 1023–1037 (2017). https://doi.org/10.1038/onc.2016.270
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2016.270
This article is cited by
-
Regulating tumor suppressor genes: post-translational modifications
Signal Transduction and Targeted Therapy (2020)
-
miR-100-3p inhibits cell proliferation and induces apoptosis in human gastric cancer through targeting to BMPR2
Cancer Cell International (2019)
-
Tumor-recruited M2 macrophages promote gastric and breast cancer metastasis via M2 macrophage-secreted CHI3L1 protein
Journal of Hematology & Oncology (2017)