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Inhibitor of growth-4 mediates chromatin modification and has a suppressive effect on tumorigenesis and innate immunity

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Tumor Biology

Abstract

Inhibitor of growth-4 (ING4) is a member of the ING family and acts as a tumor suppressor protein. ING4 is a promising candidate for cancer research due to its anti-angiogenic function and its role in the inhibition of cell migration, cell cycle, and induction of apoptosis. Interaction of this protein with the histone acetyl transferase complex plays a vital role in the regulation of multiple nuclear factor kappa light chain enhancer of activated B cells response elements and thus in the regulation of innate immunity. Splice variants of ING4 have different binding affinities to target sites, which results in the enhancement of its functional diversity. ING4 is among the few known regulatory proteins that can directly interact with chromatin as well as with transcription factors. The influence of ING4 on tumor necrosis factor-α, keratinocyte chemoattractant, interleukin (IL)-6, IL-8, matrix metalloproteinases, cyclooxygenase-2, and IκBα expression clearly demonstrates its critical role in the regulation of inflammatory mediators. Its interaction with liprin α1 and p53 contribute to mitigate cell spreading and induce apoptosis of cancer cells. Multiple factors including breast cancer melanoma suppressor-1 are upstream regulators of ING4 and are frequently deactivated in tumor cells. In the present review, the different properties of ING4 are discussed, and its activities are correlated with different aspects of cell physiology. Special emphasis is placed on our current understanding of ING4 with respect to its influence on chromatin modification, tumorigenesis, and innate immunity.

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Abbreviations

ALL:

Adult acute lymphoblastic leukemia

BCR:

B-cell receptor

BRMS1:

Breast cancer melanoma suppressor-1

COX-2:

Cyclooxygenase-2

EBV:

Epstein–Barr virus

GFR:

Growth factor receptor

H3K4me3:

H3 trimethylated at position K4

HAT:

Histone acetyl transferase

HBO1:

HAT-associated ORC1

HDAC:

Histone deacetylase

HIF:

Hypoxia-inducible factor

HNSCC:

Head and neck squamous cell carcinoma

HUVEC:

Human umbilical vein endothelial cell

IL:

Interleukin

ING4:

Inhibitor of growth-4

KC:

Keratinocyte chemoattractant

LAR:

Leukocyte common antigen-related

MCP-1:

Monocyte chemoattractant protein-1

MMP:

Metalloproteinase

NF-κB:

Nuclear factor kappa light chain enhancer of activated B cells

NLS:

Nuclear localization sequence

PHD:

Plant homeodomain

RANTES:

Regulated upon activation normal T-cell expressed and secreted

ROS:

Reactive oxygen species

RT-PCR:

Reverse transcription polymerase chain reaction

TLR:

Toll-like receptor

TNF:

Tumor necrosis factor

References

  1. Garkavtsev I, Kazarov A, Gudkov A, Riabowol K. Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation. Nat Genet. 1996;14:415–20.

    Article  PubMed  CAS  Google Scholar 

  2. Shiseki M, Nagashima M, Pedeux RM, Kitahama-Shiseki M, Miura K, Okamura S, et al. p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res. 2003;63:2373–8.

    PubMed  CAS  Google Scholar 

  3. Doyon Y, Cayrou C, Ullah M, Landry AJ, Côté V, Selleck W, et al. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell. 2006;21:51–64.

    Article  PubMed  CAS  Google Scholar 

  4. Zhang X, Xu LS, Wang ZQ, Wang KS, Li N, Cheng ZH, et al. ING4 induces G2/M cell cycle arrest and enhances the chemosensitivity to DNA-damage agents in HepG2 cells. FEBS Lett. 2004;570:7–12.

    Article  PubMed  CAS  Google Scholar 

  5. Li J, Li G. Cell cycle regulator ING4 is a suppressor of melanoma angiogenesis that is regulated by the metastasis suppressor BRMS1. Cancer Res. 2010;70:10445–53.

    Article  PubMed  CAS  Google Scholar 

  6. Cai L, Li X, Zheng S, Wang Y, Wang Y, Li H, et al. Inhibitor of growth 4 is involved in melanomagenesis and induces growth suppression and apoptosis in melanoma cell line M14. Melanoma Res. 2009;19:1–7.

    Article  PubMed  CAS  Google Scholar 

  7. Li X, Cai L, Liang M, Wang Y, Yang J, Zhao Y. ING4 induces cell growth inhibition in human lung adenocarcinoma A549 cells by means of Wnt-1/β-catenin signaling pathway. Anat Rec (Hoboken). 2008;291:593–600.

    Article  CAS  Google Scholar 

  8. Unoki M, Kumamoto K, Robles AI, Shen JC, Zheng ZM, Harris CC. A novel ING2 isoform, ING2b, synergizes with ING2a to prevent cell cycle arrest and apoptosis. FEBS Lett. 2008;582:3868–74.

    Article  PubMed  CAS  Google Scholar 

  9. Unoki M, Shen JC, Zheng ZM, Harris CC. Novel splice variants of ING4 and their possible roles in the regulation of cell growth and motility. J Biol Chem. 2006;281:677–86.

    Article  Google Scholar 

  10. Moreno A, Palacios A, Orgaz JL, Jimenez B, Blanco FJ, Palmero I. Functional impact of cancer-associated mutations in the tumor suppressor protein ING4. Carcinogenesis. 2010;31:1932–8.

    Article  PubMed  CAS  Google Scholar 

  11. Coles AH, Gannon H, Cerny A, Kurt-Jones E, Jones SN. Inhibitor of growth-4 promotes IκB promoter activation to suppress NF-κB signaling and innate immunity. Proc Natl Acad Sci USA. 2010;107:11423–8.

    Article  PubMed  CAS  Google Scholar 

  12. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70.

    Article  PubMed  CAS  Google Scholar 

  13. Karin M. Nuclear factor-κB in cancer development and progression. Nature. 2006;441:431–6.

    Article  PubMed  CAS  Google Scholar 

  14. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    Article  PubMed  CAS  Google Scholar 

  15. Shen JC, Unoki M, Ythier D, Duperray A, Varticovski L, Kumamoto K, et al. Inhibitor of growth 4 suppresses cell spreading and cell migration by interacting with a novel binding partner, liprin alpha1. Cancer Res. 2007;67:2552–8.

    Article  PubMed  CAS  Google Scholar 

  16. Zhang X, Wang KS, Wang ZQ, Xu LS, Wang QW, Chen F, et al. Nuclear localization signal of ING4 plays a key role in its binding to p53. Biochem Biophys Res Commun. 2005;331:1032–8.

    Article  PubMed  CAS  Google Scholar 

  17. Culurgioni S, Muñoz IG, Palacios A, Redondo P, Blanco FJ, Montoya G. Crystallization and preliminary X-ray diffraction analysis of the dimerization domain of the tumour suppressor ING4. Acta Cryst. 2010;66:567–70.

    Google Scholar 

  18. Saksouk N, Avvakumov N, Champagne KS, Hung T, Doyon Y, Cayrou C, et al. HBO1 HAT complexes target chromatin throughout gene coding regions via multiple PHD finger interactions with histone H3 tail. Mol Cell. 2009;33:257–65.

    Article  PubMed  CAS  Google Scholar 

  19. Palacios A, Muñoz IG, Pantoja-Uceda D, Marcaida MJ, Torres D, Martín-García JM, et al. Molecular basis of histone H3K4me3 recognition by ING4. J Biol Chem. 2008;283:15956–64.

    Article  PubMed  CAS  Google Scholar 

  20. Unoki M, Kumamoto K, Takenoshita S, Harris CC. Reviewing the current classification of inhibitor of growth family proteins. Cancer Sci. 2009;100:1173–9.

    Article  PubMed  CAS  Google Scholar 

  21. He GH, Helbing CC, Wagner MJ, Sensen CW, Riabowol K. Phylogenetic analysis of the ING family of PHD finger proteins. Mol Biol Evol. 2005;22:104–16.

    Article  PubMed  CAS  Google Scholar 

  22. Gong W, Suzuki K, Russell M, Riabowol K. Function of the ING family of PHD proteins in cancer. Int J Biochem Cell Biol. 2005;37:1054–65.

    Article  PubMed  CAS  Google Scholar 

  23. Raho G, Miranda C, Tamborini E, Pierotti MA, Greco A. Detection of novel mRNA splice variants of human ING4 tumor suppressor gene. Oncogene. 2007;26:5247–57.

    Article  PubMed  CAS  Google Scholar 

  24. Saha A, Bamidele A, Murakami M, Robertson ES. EBNA3C attenuates the function of p53 through interaction with inhibitor of growth family proteins 4 and 5. J Virol. 2011;85:2079–88.

    Article  PubMed  CAS  Google Scholar 

  25. Palacios A, Moreno A, Oliveira BL, Rivera T, Prieto J, García P, et al. The dimeric structure and the bivalent recognition of H3K4me3 by the tumor suppressor ING4 suggests a mechanism for enhanced targeting of the HBO1 complex to chromatin. J Mol Biol. 2010;396:1117–27.

    Article  PubMed  CAS  Google Scholar 

  26. Li X, Kikuchi K, Takano Y. ING genes work as tumor suppressor genes in the carcinogenesis of head and neck squamous cell carcinoma. J Oncol. 2011. doi:10.1155/2011/963614.

  27. Kim S, Chin K, Gray JW, Bishop JM. A screen for genes that suppress loss of contact inhibition: identification of ING4 as a candidate tumor suppressor gene in human cancer. Proc Natl Acad Sci USA. 2004;101:16251–6.

    Article  PubMed  CAS  Google Scholar 

  28. Taipale M, Rea S, Richter K, Vilar A, Lichter P, Imhof A, et al. hMOF histone acetyltransferase is required for histone H4 lysine 16 acetylation in mammalian cells. Mol Cell Biol. 2005;25:6798–810.

    Article  PubMed  CAS  Google Scholar 

  29. Hadnagy A, Beaulieu R, Balicki D. Histone tail modifications and noncanonical functions of histones: perspectives in cancer epigenetics. Mol Cancer Ther. 2008;7:740–8.

    Article  PubMed  CAS  Google Scholar 

  30. Foy RL, Song IY, Chitalia VC, Cohen HT, Saksouk N, Cayrou C, et al. Role of Jade-1 in the histone acetyltransferase (HAT) HBO1 complex. J Biol Chem. 2008;283:28817–26.

    Article  PubMed  CAS  Google Scholar 

  31. Hung T, Binda O, Champagne KS, Kuo AJ, Johnson K, Chang HY, et al. ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation. Mol Cell. 2009;33:248–56.

    Article  PubMed  CAS  Google Scholar 

  32. Garkavtsev I, Kozin SV, Chernova O, Xu L, Winkler F, Brown E, et al. The candidate tumour suppressor protein ING4 regulates brain tumour growth and angiogenesis. Nature. 2004;428:328–32.

    Article  PubMed  CAS  Google Scholar 

  33. Gui CY, Ngo L, Xu WS, Richon VM, Marks PA. Histone deacetylase (HDAC) inhibitor activation of p21WAF1 involves changes in promoter associated proteins, including HDAC1. Proc Natl Acad Sci USA. 2004;101:1241–6.

    Article  PubMed  CAS  Google Scholar 

  34. Advani AS, Gibson SE, Douglas E, Jin T, Zhao X, Kalaycio M, et al. Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients. BMC Cancer. 2010;10:387.

    Article  PubMed  Google Scholar 

  35. Krusche CA, Wulfing P, Kersting C, Vloet A, Bocker W, Kiesel L, et al. Histone deacetylase-1 and −3 protein expression in human breast cancer: a tissue microarray analysis. Breast Cancer Res Treat. 2005;90:15–23.

    Article  PubMed  CAS  Google Scholar 

  36. Toh Y, Ohga T, Endo K, Adachi E, Kusumoto H, Haraguchi M, et al. Expression of the metastasis-associated MTA1 protein and its relationship to deacetylation of the histone H4 in esophageal squamous cell carcinomas. Int J Cancer. 2004;110:362–7.

    Article  PubMed  CAS  Google Scholar 

  37. Marchion DC, Bicaku E, Turner JG, Schmitt ML, Morelli DR, Munster PN. HDAC2 regulates chromatin plasticity and enhances DNA vulnerability. Mol Cancer Ther. 2009;8:794–801.

    Article  PubMed  CAS  Google Scholar 

  38. Hurst DR, Edmonds MD, Welch DR. Metastamir: the field of metastasis-regulatory microRNA is spreading. Cancer Res. 2009;69:7495–8.

    Article  PubMed  CAS  Google Scholar 

  39. Kalluri R. Basement membranes: structure, assembly and role in tumor angiogenesis. Nat Rev Cancer. 2003;3:422–33.

    Article  PubMed  CAS  Google Scholar 

  40. Akhtar N, Dickerson EB, Auerbach R. The sponge/matrigel angiogenesis assay. Angiogenesis. 2002;5:75–80.

    Article  PubMed  CAS  Google Scholar 

  41. Tapia C, Zlobec I, Schneider S, Kilic E, Güth U, Bubendorf L, et al. Deletion of the inhibitor of growth 4 (ING4) tumor suppressor gene is prevalent in human epidermal growth factor 2 (HER2)-positive breast cancer. Hum Pathol. 2011;42:983–90.

    Article  PubMed  CAS  Google Scholar 

  42. Kim S, Welm AL, Bishop JM. A dominant mutant allele of the ING4 tumor suppressor found in human cancer cells exacerbates MYC-initiated mouse mammary tumorigenesis. Cancer Res. 2010;70:5155–62.

    Article  PubMed  CAS  Google Scholar 

  43. Li J, Wang Y, Wong RP, Li G. The role of ING tumor suppressors in UV stress response and melanoma progression. Curr Drug Targets. 2009;10:455–64.

    Article  PubMed  CAS  Google Scholar 

  44. Ozer A, Bruick RK. Regulation of HIF by prolyl hydroxylases: recruitment of the candidate tumor suppressor protein ING4. Cell Cycle. 2005;4:1153–6.

    Article  PubMed  CAS  Google Scholar 

  45. Nozell S, Laver T, Moseley D, Nowoslawski L, De Vos M, Atkinson GP, et al. The ING4 tumor suppressor attenuates NF-κB activity at the promoters of target genes. Mol Cell Biol. 2008;28:6632–45.

    Article  PubMed  CAS  Google Scholar 

  46. Colla S, Tagliaferri S, Morandi F, Lunghi P, Donofrio G, Martorana D, et al. The new tumor-suppressor gene inhibitor of growth family member 4 (ING4) regulates the production of proangiogenic molecules by myeloma cells and suppresses hypoxia-inducible factor-1 α (HIF-1α) activity: involvement in myeloma-induced angiogenesis. Blood. 2007;110:4464–75.

    Article  PubMed  CAS  Google Scholar 

  47. Li J, Martinka M, Li G. Role of ING4 in human melanoma cell migration, invasion and patient survival. Carcinogenesis. 2008;29:1373–9.

    Article  PubMed  Google Scholar 

  48. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002;295:2387–92.

    Article  PubMed  CAS  Google Scholar 

  49. Fromont G, Joulin V, Chantrel-Groussard K, Vallancien G, Guillonneau B, Validire P, et al. Allelic losses in localized prostate cancer: association with prognostic factors. J Urol. 2003;170:1394–7.

    Article  PubMed  CAS  Google Scholar 

  50. Serra-Pagès C, Kedersha NL, Fazikas L, Medley Q, Debant A, Streuli M. The LAR transmembrane protein tyrosine phosphatase and a coiled-coil LAR-interacting protein co-localize at focal adhesions. EMBO J. 1995;14:2827–38.

    PubMed  Google Scholar 

  51. Miller KE, DeProto J, Kaufmann N, Patel BN, Duckworth A, Van Vactor D. Direct observation demonstrates that liprin-α is required for trafficking of synaptic vesicles. Curr Biol. 2005;15:684–9.

    Article  PubMed  CAS  Google Scholar 

  52. Wang QS, Li M, Zhang LY, Jin Y, Tong DD, Yu Y, et al. Down-regulation of ING4 is associated with initiation and progression of lung cancer. Histopathology. 2010;57:271–81.

    Article  PubMed  Google Scholar 

  53. Ahn KS, Sethi G, Aggarwal BB. Nuclear factor-kappa B: from clone to clinic. Curr Mol Med. 2007;7:619–37.

    Article  PubMed  CAS  Google Scholar 

  54. Karst AM, Gao K, Nelson CC, Li G. Nuclear factor kappa B subunit p50 promotes melanoma angiogenesis by upregulating interleukin-6 expression. Int J Cancer. 2009;124:494–501.

    Article  PubMed  CAS  Google Scholar 

  55. Ma X, Becker Buscaglia LE, Barker JR, Li Y. MicroRNAs in NF-κB signaling. J Mol Cell Biol. 2011;3:159–66.

    Article  PubMed  CAS  Google Scholar 

  56. Lei X, Bai Z, Ye F, Xie J, Kim CG, Huang Y, et al. Regulation of NF-κB inhibitor IκBα and viral replication by a KSHV microRNA. Nat Cell Biol. 2010;12:193–9.

    Article  PubMed  CAS  Google Scholar 

  57. Takeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–20.

    Article  PubMed  CAS  Google Scholar 

  58. Istomin AY, Godzik A. Understanding diversity of human innate immunity receptors: analysis of surface features of leucine-rich repeat domains in NLRs and TLRs. BMC Immunol. 2008;10:48.

    Article  Google Scholar 

  59. Rothe M, Sarma V, Dixit VM, Goeddel DV. TRAF2-mediated activation of NF-κB by TNF receptor 2 and CD40. Science. 1995;269:1424–7.

    Article  PubMed  CAS  Google Scholar 

  60. Le Page C, Koumakpayi IH, Lessard L, Mes-Masson AM, Saad F. EGFR and Her-2 regulate the constitutive activation of NF-kappaB in PC-3 prostate cancer cells. Prostate. 2005;65:130–40.

    Article  PubMed  Google Scholar 

  61. Pomerantz JL, Denny EM, Baltimore D. CARD11 mediates factor-specific activation of NF-κB by the T cell receptor complex. EMBO J. 2002;21:5184–94.

    Article  PubMed  CAS  Google Scholar 

  62. Brat DJ, Bellail AC, Van Meir EG. The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-oncol. 2005;7:122–33.

    Article  PubMed  CAS  Google Scholar 

  63. Ozer A, Wu LC, Bruick RK. The candidate tumor suppressor ING4 represses activation of the hypoxia inducible factor (HIF). Proc Natl Acad Sci USA. 2005;102:7481–6.

    Article  PubMed  CAS  Google Scholar 

  64. Aggarwal BB, Shishodia S, Sandur SK, Pandey MK, Sethi G. Inflammation and cancer: how hot is the link? Biochem Pharmacol. 2006;30:1605–21.

    Article  Google Scholar 

  65. Wang Y, Li G. ING3 promotes UV-induced apoptosis via Fas/caspase-8 pathway in melanoma cells. J Biol Chem. 2006;281:11887–93.

    Article  PubMed  CAS  Google Scholar 

  66. Zhu JJ, Li FB, Zhu XF, Liao WM. The p33ING1b tumor suppressor cooperates with p53 to induce apoptosis in response to etoposide in human osteosarcoma cells. Life Sci. 2006;78:1469–77.

    Article  PubMed  CAS  Google Scholar 

  67. Li G, Piche B. ING2 in cell cycle regulation. Cell Cycle. 2010;9:3846.

    PubMed  CAS  Google Scholar 

  68. Whibley C, Pharoah PD, Hollstein M. p53 polymorphisms: cancer implications. Nat Rev Cancer. 2009;9:95–107.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1120340).

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  1. Department of Microbiology and Immunology, School of Medicine, Jeju National University, 102 Jejudaehakno, Jeju, 690-756, South Korea

    Vivek Bhakta Mathema & Young-Sang Koh

  2. Brain Korea 21 Program, Jeju National University, Jeju, South Korea

    Vivek Bhakta Mathema & Young-Sang Koh

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Mathema, V.B., Koh, YS. Inhibitor of growth-4 mediates chromatin modification and has a suppressive effect on tumorigenesis and innate immunity. Tumor Biol. 33, 1–7 (2012). https://doi.org/10.1007/s13277-011-0249-3

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