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PMID: 30093632 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

O-GlcNAcylation promotes colorectal cancer metastasis via the miR-101-O-GlcNAc/EZH2 regulatory feedback circuit.

Oncogene ·Vol. 38 ·No. 3 ·2019-00-00 ·Pages 301-316

Jiang M, Xu B, Li X, Shang Y, Chu Y, Wang W, Chen D, Wu N, Hu S, Zhang S, Li M, Wu K, Yang X, Liang J, Nie Y, Fan D

Abstract

Advanced colorectal cancer (CRC) is one of the deadliest cancers, and the 5-year survival rate of patients with metastasis is extremely low. The epithelial-mesenchymal transition (EMT) is considered essential for metastatic CRC, but the fundamental molecular basis underlying this effect remains unknown. Here, we identified that O-GlcNAcylation, a unique posttranslational modification (PTM) involved in cancer metabolic reprogramming, increased the metastatic capability of CRC. The levels of O-GlcNAcylation were increased in the metastatic CRC tissues and cell lines, which likely promoted the EMT by enhancing EZH2 protein stability and function. The CRC patients with higher levels of O-GlcNAcylation exhibited greater lymph node metastasis potential and lower overall survival. Bioinformatic analysis and luciferase reporter assays revealed that both O-GlcNAcylation transferase (OGT) and EZH2 are posttranscriptionally inhibited by microRNA-101. In addition, O-GlcNAcylation and H3K27me3 modification in the miR-101 promoter region further inhibited the transcription of miR-101, resulting in the upregulation of OGT and EZH2 in metastatic CRC, thus forming a vicious cycle. In this study, we demonstrated that O-GlcNAcylation, which is negatively regulated by microRNA-101, likely promotes CRC metastasis by enhancing EZH2 protein stability and function. Reducing O-GlcNAcylation may be a potential therapeutic strategy for metastatic CRC.

MeSH Terms
Acetylglucosamine/metabolism Adenocarcinoma/metabolism,mortality,secondary Cell Line, Tumor Colorectal Neoplasms/metabolism,mortality,pathology Enhancer of Zeste Homolog 2 Protein/metabolism Epithelial-Mesenchymal Transition/physiology Feedback, Physiological Feeding Behavior Gene Expression Regulation, Neoplastic Humans Kaplan-Meier Estimate Lymphatic Metastasis/physiopathology MicroRNAs/physiology N-Acetylglucosaminyltransferases/metabolism Neoplasm Proteins/metabolism Prognosis Promoter Regions, Genetic Proportional Hazards Models Protein Processing, Post-Translational RNA Interference RNA, Small Interfering/genetics Transcription, Genetic
Chemicals
MIRN101 microRNA, human MicroRNAs Neoplasm Proteins RNA, Small Interfering EZH2 protein, human Enhancer of Zeste Homolog 2 Protein N-Acetylglucosaminyltransferases OGT protein, human Acetylglucosamine
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Jiang Mingzuo
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Xu Bing
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China. | Department of Gastroenterology, Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, Shaanxi Province, China.
Li Xiaowei
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Shang Yulong
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Chu Yi
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Wang Weijie
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Chen Di
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Wu Nan
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China. | Lab of Tissue Engineering, Faculty of Life Science, Northwest University, Xi'an, China.
Hu Sijun
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Zhang Song
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Li Mengbin
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Wu Kaichun
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Yang Xiaoyong ORCID
Department of molecular cellular and developmental biology, Yale University, New Haven, USA.
Liang Jie
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
Nie Yongzhan
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China. yongznie@fmmu.edu.cn.
Fan Daiming
State key Laboratory of Cancer Biology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China. daimingfan@fmmu.edu.cn.
References (59)
59 references, click to expand
  1. Cytoplasmic O-glycosylation prevents cell surface transport of E-cadherin during apoptosis.
    EMBO J. 2001 Nov 1;20(21):5999-6007 PMID: 11689440
  2. Polyamine metabolism in primary human colon adenocarcinoma cells (SW480) and their lymph node metastatic derivatives (SW620).
    Amino Acids. 2003;24(1-2):63-72 PMID: 12624736
  3. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited.
    Nat Rev Cancer. 2003 Jun;3(6):453-8 PMID: 12778135
  4. Role of microRNAs in plant and animal development.
    Science. 2003 Jul 18;301(5631):336-8 PMID: 12869753
  5. Perturbations in O-linked beta-N-acetylglucosamine protein modification cause severe defects in mitotic progression and cytokinesis.
    J Biol Chem. 2005 Sep 23;280(38):32944-56 PMID: 16027160
  6. The hexosamine signaling pathway: deciphering the "O-GlcNAc code".
    Sci STKE. 2005 Nov 29;2005(312):re13 PMID: 16317114
  7. Modification of p53 with O-linked N-acetylglucosamine regulates p53 activity and stability.
    Nat Cell Biol. 2006 Oct;8(10):1074-83 PMID: 16964247
  8. Cycling of O-linked beta-N-acetylglucosamine on nucleocytoplasmic proteins.
    Nature. 2007 Apr 26;446(7139):1017-22 PMID: 17460662
  9. The role of obesity and related metabolic disturbances in cancers of the colon, prostate, and pancreas.
    Gastroenterology. 2007 May;132(6):2208-25 PMID: 17498513
  10. Priorities in colorectal cancer research: recommendations from the Gastrointestinal Scientific Leadership Council of the Coalition of Cancer Cooperative Groups.
    J Clin Oncol. 2007 Jun 1;25(16):2313-21 PMID: 17538178
  11. O-linked beta-N-acetylglucosamine (O-GlcNAc): Extensive crosstalk with phosphorylation to regulate signaling and transcription in response to nutrients and stress.
    Biochim Biophys Acta. 2010 Feb;1800(2):96-106 PMID: 19647786
  12. Modulation of transcription factor function by O-GlcNAc modification.
    Biochim Biophys Acta. 2010 May-Jun;1799(5-6):353-64 PMID: 20202486
  13. Snail1 is stabilized by O-GlcNAc modification in hyperglycaemic condition.
    EMBO J. 2010 Nov 17;29(22):3787-96 PMID: 20959806
  14. CDK1-dependent phosphorylation of EZH2 suppresses methylation of H3K27 and promotes osteogenic differentiation of human mesenchymal stem cells.
    Nat Cell Biol. 2011 Jan;13(1):87-94 PMID: 21131960
  15. O-GlcNAcylation is a novel regulator of lung and colon cancer malignancy.
    Biochim Biophys Acta. 2011 Apr;1812(4):514-9 PMID: 21255644
  16. Hallmarks of cancer: the next generation.
    Cell. 2011 Mar 4;144(5):646-74 PMID: 21376230
  17. Cyclin-dependent kinase 1 (CDK1)-mediated phosphorylation of enhancer of zeste 2 (Ezh2) regulates its stability.
    J Biol Chem. 2011 Aug 12;286(32):28511-9 PMID: 21659531
  18. Multiple post-translational modifications regulate E-cadherin transport during apoptosis.
    J Cell Sci. 2012 Jun 1;125(Pt 11):2615-25 PMID: 22375065
  19. Diabetes-associated angiotensin activation enhances liver metastasis of colon cancer.
    Clin Exp Metastasis. 2012 Dec;29(8):915-25 PMID: 22552372
  20. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability.
    Cell Metab. 2012 Aug 8;16(2):226-37 PMID: 22883232
  21. A correlation between altered O-GlcNAcylation, migration and with changes in E-cadherin levels in ovarian cancer cells.
    Exp Cell Res. 2013 Jun 10;319(10):1482-90 PMID: 23524144
  22. The impact of glycemic levels in patients with colon cancer.
    Clin Adv Hematol Oncol. 2013 Feb;11(2):93-4 PMID: 23598910
  23. Cracking the O-GlcNAc code in metabolism.
    Trends Endocrinol Metab. 2013 Jun;24(6):301-9 PMID: 23647930
  24. O-GlcNAc transferase integrates metabolic pathways to regulate the stability of c-MYC in human prostate cancer cells.
    Cancer Res. 2013 Aug 15;73(16):5277-87 PMID: 23720054
  25. Sox4 is a master regulator of epithelial-mesenchymal transition by controlling Ezh2 expression and epigenetic reprogramming.
    Cancer Cell. 2013 Jun 10;23(6):768-83 PMID: 23764001
  26. Regulation of protein degradation by O-GlcNAcylation: crosstalk with ubiquitination.
    Mol Cell Proteomics. 2013 Dec;12(12):3489-97 PMID: 23824911
  27. O-GlcNAc in cancer biology.
    Amino Acids. 2013 Oct;45(4):719-33 PMID: 23836420
  28. O-GlcNAcylation: A New Cancer Hallmark?
    Front Endocrinol (Lausanne). 2013 Aug 12;4:99 PMID: 23964270
  29. c-Myc-mediated epigenetic silencing of MicroRNA-101 contributes to dysregulation of multiple pathways in hepatocellular carcinoma.
    Hepatology. 2014 May;59(5):1850-63 PMID: 24002871
  30. Colorectal cancer.
    Lancet. 2014 Apr 26;383(9927):1490-1502 PMID: 24225001
  31. O-GlcNAcylation regulates EZH2 protein stability and function.
    Proc Natl Acad Sci U S A. 2014 Jan 28;111(4):1355-60 PMID: 24474760
  32. Colorectal cancer statistics, 2014.
    CA Cancer J Clin. 2014 Mar-Apr;64(2):104-17 PMID: 24639052
  33. O-GlcNAcylation regulates cancer metabolism and survival stress signaling via regulation of the HIF-1 pathway.
    Mol Cell. 2014 Jun 5;54(5):820-31 PMID: 24857547
  34. Matrigel: from discovery and ECM mimicry to assays and models for cancer research.
    Adv Drug Deliv Rev. 2014 Dec 15;79-80:3-18 PMID: 24997339
  35. Systemic miRNA-7 delivery inhibits tumor angiogenesis and growth in murine xenograft glioblastoma.
    Oncotarget. 2014 Aug 30;5(16):6687-700 PMID: 25149532
  36. Three Decades of Research on O-GlcNAcylation - A Major Nutrient Sensor That Regulates Signaling, Transcription and Cellular Metabolism.
    Front Endocrinol (Lausanne). 2014 Oct 27;5:183 PMID: 25386167
  37. Aberrant O-GlcNAcylated Proteins: New Perspectives in Breast and Colorectal Cancer.
    Front Endocrinol (Lausanne). 2014 Nov 11;5:193 PMID: 25426101
  38. STIM1, a direct target of microRNA-185, promotes tumor metastasis and is associated with poor prognosis in colorectal cancer.
    Oncogene. 2015 Sep 10;34(37):4808-20 PMID: 25531324
  39. mTOR/MYC Axis Regulates O-GlcNAc Transferase Expression and O-GlcNAcylation in Breast Cancer.
    Mol Cancer Res. 2015 May;13(5):923-33 PMID: 25636967
  40. Systemic delivery of microRNA-101 potently inhibits hepatocellular carcinoma in vivo by repressing multiple targets.
    PLoS Genet. 2015 Feb 18;11(2):e1004873 PMID: 25693145
  41. MicroRNA-423-5p targets O-GlcNAc transferase to induce apoptosis in cardiomyocytes.
    Mol Med Rep. 2015 Jul;12(1):1163-8 PMID: 25776937
  42. Elevated O-GlcNAcylation promotes colonic inflammation and tumorigenesis by modulating NF-κB signaling.
    Oncotarget. 2015 May 20;6(14):12529-42 PMID: 25915426
  43. MicroRNAs as Regulator of Signaling Networks in Metastatic Colon Cancer.
    Biomed Res Int. 2015;2015:823620 PMID: 26064956
  44. MicroRNA-424 Predicts a Role for β-1,4 Branched Glycosylation in Cell Cycle Progression.
    J Biol Chem. 2016 Jan 15;291(3):1529-37 PMID: 26589799
  45. Targeting EZH2 in cancer.
    Nat Med. 2016 Feb;22(2):128-34 PMID: 26845405
  46. Silencing the Nucleocytoplasmic O-GlcNAc Transferase Reduces Proliferation, Adhesion, and Migration of Cancer and Fetal Human Colon Cell Lines.
    Front Endocrinol (Lausanne). 2016 May 25;7:46 PMID: 27252680
  47. O-GlcNAcylation regulates breast cancer metastasis via SIRT1 modulation of FOXM1 pathway.
    Oncogene. 2017 Jan 26;36(4):559-569 PMID: 27345396
  48. Regulation of OGT by URI in Response to Glucose Confers c-MYC-Dependent Survival Mechanisms.
    Cancer Cell. 2016 Aug 8;30(2):290-307 PMID: 27505673
  49. Elevated O-GlcNAcylation promotes gastric cancer cells proliferation by modulating cell cycle related proteins and ERK 1/2 signaling.
    Oncotarget. 2016 Sep 20;7(38):61390-61402 PMID: 27542217
  50. Recently discovered EZH2 and EHMT2 (G9a) inhibitors.
    Future Med Chem. 2016 Sep;8(13):1635-54 PMID: 27548656
  51. The role of microRNAs in colorectal cancer.
    Biomed Pharmacother. 2016 Dec;84:705-713 PMID: 27701052
  52. Loss of the histone methyltransferase EZH2 induces resistance to multiple drugs in acute myeloid leukemia.
    Nat Med. 2017 Jan;23(1):69-78 PMID: 27941792
  53. O-Linked N-Acetylglucosamine (O-GlcNAc) Expression Levels Epigenetically Regulate Colon Cancer Tumorigenesis by Affecting the Cancer Stem Cell Compartment via Modulating Expression of Transcriptional Factor MYBL1.
    J Biol Chem. 2017 Mar 10;292(10):4123-4137 PMID: 28096468
  54. ERK2-ZEB1-miR-101-1 axis contributes to epithelial-mesenchymal transition and cell migration in cancer.
    Cancer Lett. 2017 Apr 10;391:59-73 PMID: 28109909
  55. Hyperglycemia exacerbates colon cancer malignancy through hexosamine biosynthetic pathway.
    Oncogenesis. 2017 Mar 20;6(3):e306 PMID: 28319096
  56. O-GlcNAc transferase promotes fatty liver-associated liver cancer through inducing palmitic acid and activating endoplasmic reticulum stress.
    J Hepatol. 2017 Aug;67(2):310-320 PMID: 28347804
  57. [The Role of MicroRNAs in Colorectal Cancer].
    Korean J Gastroenterol. 2017 Apr 25;69(4):206-211 PMID: 28449421
  58. O-GlcNAcylation affects β-catenin and E-cadherin expression, cell motility and tumorigenicity of colorectal cancer.
    Exp Cell Res. 2018 Mar 1;364(1):42-49 PMID: 29391154
  59. Cross regulation between mTOR signaling and O-GlcNAcylation.
    J Bioenerg Biomembr. 2018 Jun;50(3):213-222 PMID: 29524020
Article Info
Journal
Oncogene
Abbr.
Oncogene
ISSN
1476-5594
DOI
10.1038/s41388-018-0435-5
Email
yongznie@fmmu.edu.cn
daimingfan@fmmu.edu.cn
Published
2019-00-00
Epub
2018-00-09
Pages
301-316
Language
English
Region
England
NLM ID
8711562
PMCID
PMC6336687
Subset
IM
Grants
National Natural Science Foundation of China (National Science Foundation of China) · 81730016 · International
National Natural Science Foundation of China (National Science Foundation of China) · 81421003 · International
National Natural Science Foundation of China (National Science Foundation of China) · 81772650 · International
National Natural Science Foundation of China (National Science Foundation of China) · 81430072 · International
Corrections
ErratumIn
PMID: 31160652
External Links
PubMed source DOI: 10.1038/s41388-018-0435-5 PMC Full Text View journal details
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