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5-Azacytidine engages an IRE1α-EGFR-ERK1/2 signaling pathway that stabilizes the LDL receptor mRNA

Mnasri, Nourhen, Mamarbachi, Maya, Allen, Bruce G., Mayer, Gaétan·2018·Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
DOI 10.1016/j.bbagrm.2017.11.010
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Abstract

Hepatic low-density lipoprotein receptor (LDLR) is the primary conduit for the clearance of plasma LDL-cholesterol and increasing its expression represents a central goal for treating cardiovascular disease. However, LDLR mRNA is unstable and undergoes rapid turnover mainly due to the three AU-rich elements (ARE) in its proximal 3'-untranslated region (3'-UTR). Herein, our data revealed that 5-azacytidine (5-AzaC), an antimetabolite used in the treatment of myelodysplastic syndrome, stabilizes the LDLR mRNA through a previously unrecognized signaling pathway resulting in a strong increase of its protein level in human hepatocytes in culture. 5-AzaC caused a sustained activation of the inositol-requiring enzyme 1α (IRE1α) kinase domain and c-Jun N-terminal kinase (JNK) independently of endoplasmic reticulum stress. This resulted in activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase1/2 (ERK1/2) that, in turn, stabilized LDLR mRNA. Systematic mutation of the AREs (ARE1-3) in the LDLR 3'UTR and expression of each mutant coupled to a luciferase reporter in Huh7 cells demonstrated that ARE1 is required for rapid LDLR mRNA decay and 5-AzaC-induced mRNA stabilization via the IRE1α-EGFR-ERK1/2 signaling cascade. The characterization of this pathway will help to reveal potential targets to enhance plasma LDL clearance and novel cholesterol-lowering therapeutic strategies.

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  • Different research groups have identified more than ten different compounds that enhance LDLR mRNA stability and subsequently increase LDLR protein levels, although the mechanisms and specificity are not fully understood.

    “Adding to the complexity of LDLR mRNA regulation, different research groups have identified more than ten different compounds that enhance LDLR mRNA stability and subsequently increase LDLR protein levels, although the mechanism(s) behind these effects and how specific they are is not yet fully understood [19,21,24,32,[35][36][37][38][39][40][41].”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [24]

  • The LDLR mRNA features four UCAU sequences located between ARE1 and ARE2 within its 3′UTR.

    “The LDLR mRNA features four such UCAU sequences located between ARE1 and ARE2 within its 3′UTR [24,32].”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [24]

  • Some studies suggest that the increase in LDLR mRNA stability may depend on the presence of ARE1, the UCAU sequences, and the RBP HuR.

    “Some studies suggest that this increase may depend on the presence of ARE1, the UCAU sequences, and the RBP HuR [24,40].”

    From The low-density lipoprotein receptor: Emerging post-transcriptional regulatory mechanisms (2025) · cites this paper as [24]

  • Triciribine shares with berberine and 5-AzaC the traits of inhibition of DNA synthesis, induction of ERK activity, stabilization of LDLR mRNA, and inhibition of PCSK9 expression.

    “Interestingly, triciribine shares a number of similar traits with berberine and 5-AzaC: 1) inhibition of DNA synthesis, 2) induction of ERK activity, 3) stabilization of LDLR mRNA and 4) inhibition of PCSK9 expression11,34,35,49–51.”

    From Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA (2018) · cites this paper as [34]

  • The effects of triciribine on LDLR mRNA stability and PCSK9 levels were reminiscent of those elicited by berberine and 5-Azacytidine (5-AzaC).

    “The effects of triciribine on LDLR mRNA stability and PCSK9 levels were reminiscent of those elicited by berberine and 5-Azacytidine (5-AzaC)11,34,35.”

    From Triciribine increases LDLR expression and LDL uptake through stabilization of LDLR mRNA (2018) · cites this paper as [34]

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Research works printed but not linked: 58

  1. Abdelmohsen, 2007, Phosphorylation of HuR by Chk2 regulates SIRT1 expression, Mol. Cell, 25, 543, 10.1016/j.molcel.2007.01.011 · DOI
  2. Abidi, 2006, The medicinal plant goldenseal is a natural LDL-lowering agent with multiple bioactive components and new action mechanisms, J. Lipid Res., 47, 2134, 10.1194/jlr.M600195-JLR200 · DOI · Paper page
  3. Auf, 2013, High epiregulin expression in human U87 glioma cells relies on IRE1alpha and promotes autocrine growth through EGF receptor, BMC Cancer, 13, 597, 10.1186/1471-2407-13-597 · DOI
  4. Baigent, 2010, Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials, Lancet, 376, 1670, 10.1016/S0140-6736(10)61350-5 · DOI · Paper page
  5. Barreau, 2005, AU-rich elements and associated factors: are there unifying principles?, Nucleic Acids Res., 33, 7138, 10.1093/nar/gki1012 · DOI · Paper page
  6. Berasain, 2014, Amphiregulin, Semin. Cell Dev. Biol., 28, 31, 10.1016/j.semcdb.2014.01.005 · DOI
  7. Bouhairie, 2015, Familial hypercholesterolemia, Cardiol. Clin., 33, 169, 10.1016/j.ccl.2015.01.001 · DOI
  8. Bridges, 1996, Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor, J. Med. Chem., 39, 267, 10.1021/jm9503613 · DOI
  9. Brown, 1999, A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood, Proc. Natl. Acad. Sci. U. S. A., 96, 11041, 10.1073/pnas.96.20.11041 · DOI · Paper page
  10. Caput, 1986, Identification of a common nucleotide sequence in the 3′-untranslated region of mRNA molecules specifying inflammatory mediators, Proc. Natl. Acad. Sci. U. S. A., 83, 1670, 10.1073/pnas.83.6.1670 · DOI
  11. Chen, 1998, Stabilization of interleukin-2 mRNA by the c-Jun NH2-terminal kinase pathway, Science, 280, 1945, 10.1126/science.280.5371.1945 · DOI
  12. De Castro-Oros, 2010, The genetic basis of familial hypercholesterolemia: inheritance, linkage, and mutations, Appl. Clin. Genet., 3, 53
  13. Estey, 2013, Epigenetics in clinical practice: the examples of azacitidine and decitabine in myelodysplasia and acute myeloid leukemia, Leukemia, 27, 1803, 10.1038/leu.2013.173 · DOI
  14. Gherzi, 2004, A KH domain RNA binding protein, KSRP, promotes ARE-directed mRNA turnover by recruiting the degradation machinery, Mol. Cell, 14, 571, 10.1016/j.molcel.2004.05.002 · DOI
  15. Ghosh, 2014, Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress, Cell, 158, 534, 10.1016/j.cell.2014.07.002 · DOI
  16. Goldstein, 2009, The LDL receptor, Arterioscler. Thromb. Vasc. Biol., 29, 431, 10.1161/ATVBAHA.108.179564 · DOI · Paper page
  17. Goto, 1997, Upregulation of low density lipoprotein receptor by gemfibrozil, a hypolipidemic agent, in human hepatoma cells through stabilization of mRNA transcripts, Arterioscler. Thromb. Vasc. Biol., 17, 2707, 10.1161/01.ATV.17.11.2707 · DOI · Paper page
  18. Hetz, 2012, The unfolded protein response: controlling cell fate decisions under ER stress and beyond, Nat. Rev. Mol. Cell Biol., 13, 89, 10.1038/nrm3270 · DOI
  19. Hitti, 2006, Mitogen-activated protein kinase-activated protein kinase 2 regulates tumor necrosis factor mRNA stability and translation mainly by altering tristetraprolin expression, stability, and binding to adenine/uridine-rich element, Mol. Cell. Biol., 26, 2399, 10.1128/MCB.26.6.2399-2407.2006 · DOI
  20. Horton, 2003, Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes, Proc. Natl. Acad. Sci. U. S. A., 100, 12027, 10.1073/pnas.1534923100 · DOI · Paper page
  21. Knouff, 2001, Doubling expression of the low density lipoprotein receptor by truncation of the 3′-untranslated region sequence ameliorates type iii hyperlipoproteinemia in mice expressing the human apoe2 isoform, J. Biol. Chem., 276, 3856, 10.1074/jbc.M009423200 · DOI · Paper page
  22. Korhonen, 2007, Post-transcriptional regulation of human inducible nitric-oxide synthase expression by the Jun N-terminal kinase, Mol. Pharmacol., 71, 1427, 10.1124/mol.106.033449 · DOI
  23. Kyriakis, 1994, The stress-activated protein kinase subfamily of c-Jun kinases, Nature, 369, 156, 10.1038/369156a0 · DOI
  24. Li, 2009, Identification of mRNA binding proteins that regulate the stability of LDL receptor mRNA through AU-rich elements, J. Lipid Res., 50, 820, 10.1194/jlr.M800375-JLR200 · DOI · Paper page
  25. Malo, 2010, Tauroursodeoxycholic acid reduces endoplasmic reticulum stress, trypsin activation, and acinar cell apoptosis while increasing secretion in rat pancreatic acini, Am. J. Physiol. Gastrointest. Liver Physiol., 299, G877, 10.1152/ajpgi.00423.2009 · DOI
  26. Maxwell, 2003, Novel putative SREBP and LXR target genes identified by microarray analysis in liver of cholesterol-fed mice, J. Lipid Res., 44, 2109, 10.1194/jlr.M300203-JLR200 · DOI · Paper page
  27. McCubrey, 2007, Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance, Biochim. Biophys. Acta, 1773, 1263, 10.1016/j.bbamcr.2006.10.001 · DOI
  28. McKay, 2007, Integrating signals from RTKs to ERK/MAPK, Oncogene, 26, 3113, 10.1038/sj.onc.1210394 · DOI
  29. Mendez, 2015, Endoplasmic reticulum stress-independent activation of unfolded protein response kinases by a small molecule ATP-mimic, elife, 4, 10.7554/eLife.05434 · DOI
  30. Meng, 2015, Amphiregulin may be a new biomarker of classically activated macrophages, Biochem. Biophys. Res. Commun., 466, 393, 10.1016/j.bbrc.2015.09.037 · DOI
  31. Ming, 1998, c-jun N-terminal kinase is involved in AUUUA-mediated interleukin-3 mRNA turnover in mast cells, EMBO J., 17, 6039, 10.1093/emboj/17.20.6039 · DOI
  32. Nakahara, 2002, Bile acids enhance low density lipoprotein receptor gene expression via a MAPK cascade-mediated stabilization of mRNA, J. Biol. Chem., 277, 37229, 10.1074/jbc.M206749200 · DOI · Paper page
  33. O'Keefe, 2004, Optimal low-density lipoprotein is 50 to 70mg/dl: lower is better and physiologically normal, J. Am. Coll. Cardiol., 43, 2142, 10.1016/j.jacc.2004.03.046 · DOI
  34. Papa, 2003, Bypassing a kinase activity with an ATP-competitive drug, Science, 302, 1533, 10.1126/science.1090031 · DOI
  35. Papandreou, 2011, Identification of an Ire1alpha endonuclease specific inhibitor with cytotoxic activity against human multiple myeloma, Blood, 117, 1311, 10.1182/blood-2010-08-303099 · DOI · Paper page
  36. Poirier, 2013, The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol, Drug Des. Devel. Ther., 7, 1135
  37. Poirier, 2014, The epigenetic drug 5-azacytidine interferes with cholesterol and lipid metabolism, J. Biol. Chem., 289, 18736, 10.1074/jbc.M114.563650 · DOI · Paper page
  38. Riese, 2014, Epiregulin: roles in normal physiology and cancer, Semin. Cell Dev. Biol., 28, 49, 10.1016/j.semcdb.2014.03.005 · DOI
  39. Roberts, 2007, Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer, Oncogene, 26, 3291, 10.1038/sj.onc.1210422 · DOI · Paper page
  40. Rosenbloom, 2013, ENCODE data in the UCSC genome browser: year 5 update, Nucleic Acids Res., 41, D56, 10.1093/nar/gks1172 · DOI
  41. Shaw, 1986, A conserved AU sequence from the 3′ untranslated region of GM-CSF mRNA mediates selective mRNA degradation, Cell, 46, 659, 10.1016/0092-8674(86)90341-7 · DOI
  42. Spady, 1992, Hepatic clearance of plasma low density lipoproteins, Semin. Liver Dis., 12, 373, 10.1055/s-2008-1040407 · DOI · Paper page
  43. Srivastava, 1999, Bcl-2 and Bcl-X(L) block thapsigargin-induced nitric oxide generation, c-Jun NH(2)-terminal kinase activity, and apoptosis, Mol. Cell. Biol., 19, 5659, 10.1128/MCB.19.8.5659 · DOI
  44. Sugiura, 2003, Feedback regulation of MAPK signalling by an RNA-binding protein, Nature, 424, 961, 10.1038/nature01907 · DOI
  45. Teslovich, 2010, Biological, clinical and population relevance of 95 loci for blood lipids, Nature, 466, 707, 10.1038/nature09270 · DOI · Paper page
  46. Tirasophon, 2000, The endoribonuclease activity of mammalian IRE1 autoregulates its mRNA and is required for the unfolded protein response, Genes Dev., 14, 2725, 10.1101/gad.839400 · DOI
  47. Urano, 2000, Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1, Science, 287, 664, 10.1126/science.287.5453.664 · DOI
  48. Vargas, 2009, Protein kinase C activation stabilizes LDL receptor mRNA via the JNK pathway in HepG2 cells, J. Lipid Res., 50, 386, 10.1194/jlr.M800316-JLR200 · DOI
  49. Verin, 2000, Role of ras-dependent ERK activation in phorbol ester-induced endothelial cell barrier dysfunction, Am. J. Phys. Lung Cell. Mol. Phys., 279, L360
  50. Wilson, 1997, Modulation of LDL receptor mRNA stability by phorbol esters in human liver cell culture models, J. Lipid Res., 38, 437, 10.1016/S0022-2275(20)37252-7 · DOI · Paper page
  51. Wilson, 1998, Stabilization and cytoskeletal-association of LDL receptor mRNA are mediated by distinct domains in its 3′ untranslated region, J. Lipid Res., 39, 1025, 10.1016/S0022-2275(20)33870-0 · DOI · Paper page
  52. Yashiro, 2013, 5-Aminoimidazole-4-carboxamide ribonucleoside stabilizes low density lipoprotein receptor mRNA in hepatocytes via ERK-dependent HuR binding to an AU-rich element, Atherosclerosis, 226, 95, 10.1016/j.atherosclerosis.2012.09.033 · DOI · Paper page
  53. Yashiro, 2011, Chenodeoxycholic acid stabilization of LDL receptor mRNA depends on 3′-untranslated region and AU-rich element-binding protein, Biochem. Biophys. Res. Commun., 409, 155, 10.1016/j.bbrc.2011.04.006 · DOI · Paper page
  54. Yoshida, 2001, XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor, Cell, 107, 881, 10.1016/S0092-8674(01)00611-0 · DOI
  55. Zelcer, 2009, LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor, Science, 325, 100, 10.1126/science.1168974 · DOI · Paper page
  56. Zhou, 2001, Role of AMP-activated protein kinase in mechanism of metformin action, J. Clin. Invest., 108, 1167, 10.1172/JCI13505 · DOI · Paper page
  57. Zubiaga, 1995, The nonamer UUAUUUAUU is the key AU-rich sequence motif that mediates mRNA degradation, Mol. Cell. Biol., 15, 2219, 10.1128/MCB.15.4.2219 · DOI
  58. Zwang, 2009, Systems biology of growth factor-induced receptor endocytosis, Traffic, 10, 349, 10.1111/j.1600-0854.2008.00870.x · DOI

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Metadata

Authors
Mnasri, N., Mamarbachi, M., Allen, B. G., & Mayer, G.
Venue
Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Publisher
Elsevier BV
Published
2018-01
Volume
1861
Issue
1
Pages
29-40
ISSN
1874-9399
DOI
10.1016/j.bbagrm.2017.11.010
Cited by
12
References
5
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Funders
  • Canadian Institutes of Health Research (MOP133598)
  • FRQS (32877)
  • Montreal Heart Institute Foundation

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