Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Medicine
Published in: BMC Medicine 1/2017

Open Access 01-12-2017 | Research article

ING3 promotes prostate cancer growth by activating the androgen receptor

Authors: Arash Nabbi, Urszula L. McClurg, Subhash Thalappilly, Amal Almami, Mahsa Mobahat, Tarek A. Bismar, Olivier Binda, Karl T. Riabowol

Published in: BMC Medicine | Issue 1/2017

Login to get access

Abstract

Background

The androgen receptor (AR) is a major driver of prostate cancer, and increased AR levels and co-activators of the receptor promote the development of prostate cancer. INhibitor of Growth (ING) proteins target lysine acetyltransferase or lysine deacetylase complexes to the histone H3K4Me3 mark of active transcription, to affect chromatin structure and gene expression. ING3 is a stoichiometric member of the TIP60 lysine acetyltransferase complex implicated in prostate cancer development.

Methods

Biopsies of 265 patients with prostate cancer were stained for ING3, pan-cytokeratin, and DNA. LNCaP and C4-2 androgen-responsive cells were used for in vitro assays including immunoprecipitation, western blotting, Luciferase reporter assay and quantitative polymerase chain reaction. Cell viability and migration assays were performed in prostate cancer cell lines using scrambled siRNA or siRNA targeting ING3.

Results

We find that ING3 levels and AR activity positively correlate in prostate cancer. ING3 potentiates androgen effects, increasing expression of androgen-regulated genes and androgen response element-driven reporters to promote growth and anchorage-independent growth. Conversely, ING3 knockdown inhibits prostate cancer cell growth and invasion. ING3 activates the AR by serving as a scaffold to increase interaction between TIP60 and the AR in the cytoplasm, enhancing receptor acetylation and translocation to the nucleus. Activation is independent of ING3's ability to target the TIP60 complex to H3K4Me3, identifying a previously unknown chromatin-independent cytoplasmic activity for ING3. In agreement with in vitro observations, analysis of The Cancer Genome Atlas (TCGA) data (n = 498) and a prostate cancer tissue microarray (n = 256) show that ING3 levels are higher in aggressive prostate cancers, with high levels of ING3 predicting shorter patient survival in a low AR subgroup. Including ING3 levels with currently used indicators such as the Gleason score provides more accurate prognosis in primary prostate cancer.

Conclusions

In contrast to the majority of previous reports suggesting tumor suppressive functions in other cancers, our observations identify a clear oncogenic role for ING3, which acts as a co-activator of AR in prostate cancer. Data from TCGA and our previous and current tissue microarrays suggest that ING3 levels correlate with AR levels and that in patients with low levels of the receptor, ING3 level could serve as a useful prognostic biomarker.
Appendix
Available only for authorised users
Literature
1.
2.
Gleave ME, Bruchovsky N, Moore MJ, Venner P. Prostate cancer: 9. Treatment of advanced disease. CMAJ. 1999;160(2):225–32.PubMedPubMedCentral
3.
Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15(12):701–11.CrossRefPubMedPubMedCentral
4.
Culig Z, Comuzzi B, Steiner H, Bartsch G, Hobisch A. Expression and function of androgen receptor coactivators in prostate cancer. J Steroid Biochem Mol Biol. 2004;92(4):265–71.CrossRefPubMed
5.
Tien JC, Liu Z, Liao L, Wang F, Xu Y, Wu YL, Zhou N, Ittmann M, Xu J. The steroid receptor coactivator-3 is required for the development of castration-resistant prostate cancer. Cancer Res. 2013;73(13):3997–4008.CrossRefPubMedPubMedCentral
6.
Karantanos T, Corn PG, Thompson TC. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene. 2013;32(49):5501–11.CrossRefPubMedPubMedCentral
7.
Jia L, Khalid O, Frenkel B, Coetzee GA. Chromatin remodeling and androgen receptor-mediated transcription. In: Mohler J, Tindall D, editors. Androgen action in prostate cancer. New York: Springer; 2009. p. 405–26.CrossRef
8.
Fu M, Rao M, Wang C, Sakamaki T, Wang J, Di Vizio D, Zhang X, Albanese C, Balk S, Chang C, et al. Acetylation of androgen receptor enhances coactivator binding and promotes prostate cancer cell growth. Mol Cell Biol. 2003;23(23):8563–75.CrossRefPubMedPubMedCentral
9.
Zhong J, Ding L, Bohrer LR, Pan Y, Liu P, Zhang J, Sebo TJ, Karnes RJ, Tindall DJ, van Deursen J, et al. p300 acetyltransferase regulates androgen receptor degradation and PTEN-deficient prostate tumorigenesis. Cancer Res. 2014;74(6):1870–80.CrossRefPubMedPubMedCentral
10.
Gaughan L, Logan IR, Cook S, Neal DE, Robson CN. Tip60 and histone deacetylase 1 regulate androgen receptor activity through changes to the acetylation status of the receptor. J Biol Chem. 2002;277(29):25904–13.CrossRefPubMed
11.
Halkidou K, Gnanapragasam VJ, Mehta PB, Logan IR, Brady ME, Cook S, Leung HY, Neal DE, Robson CN. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development. Oncogene. 2003;22(16):2466–77.CrossRefPubMed
12.
Fu M, Wang C, Reutens AT, Wang J, Angeletti RH, Siconolfi-Baez L, Ogryzko V, Avantaggiati ML, Pestell RG. p300 and p300/cAMP-response element-binding protein-associated factor acetylate the androgen receptor at sites governing hormone-dependent transactivation. J Biol Chem. 2000;275(27):20853–60.CrossRefPubMed
13.
Garkavtsev I, Kazarov A, Gudkov A, Riabowol K. Suppression of the novel growth inhibitor p33ING1 promotes neoplastic transformation. Nat Genet. 1996;14(4):415–20.CrossRefPubMed
14.
Nagashima M, Shiseki M, Miura K, Hagiwara K, Linke SP, Pedeux R, Wang XW, Yokota J, Riabowol K, Harris CC. DNA damage-inducible gene p33ING2 negatively regulates cell proliferation through acetylation of p53. Proc Natl Acad Sci U S A. 2001;98(17):9671–6.CrossRefPubMedPubMedCentral
15.
Nagashima M, Shiseki M, Pedeux RM, Okamura S, Kitahama-Shiseki M, Miura K, Yokota J, Harris CC. A novel PHD-finger motif protein, p47ING3, modulates p53-mediated transcription, cell cycle control, and apoptosis. Oncogene. 2003;22(3):343–50.CrossRefPubMed
16.
Shiseki M, Nagashima M, Pedeux RM, Kitahama-Shiseki M, Miura K, Okamura S, Onogi H, Higashimoto Y, Appella E, Yokota J, et al. p29ING4 and p28ING5 bind to p53 and p300, and enhance p53 activity. Cancer Res. 2003;63(10):2373–8.PubMed
17.
Doyon Y, Cayrou C, Ullah M, Landry AJ, Cote V, Selleck W, Lane WS, Tan S, Yang XJ, Cote J. ING tumor suppressor proteins are critical regulators of chromatin acetylation required for genome expression and perpetuation. Mol Cell. 2006;21(1):51–64.CrossRefPubMed
18.
Pena PV, Davrazou F, Shi X, Walter KL, Verkhusha VV, Gozani O, Zhao R, Kutateladze TG. Molecular mechanism of histone H3K4me3 recognition by plant homeodomain of ING2. Nature. 2006;442(7098):100–3.PubMedPubMedCentral
19.
Loewith R, Meijer M, Lees-Miller SP, Riabowol K, Young D. Three yeast proteins related to the human candidate tumor suppressor p33(ING1) are associated with histone acetyltransferase activities. Mol Cell Biol. 2000;20(11):3807–16.CrossRefPubMedPubMedCentral
20.
Doyon Y, Selleck W, Lane WS, Tan S, Cote J. Structural and functional conservation of the NuA4 histone acetyltransferase complex from yeast to humans. Mol Cell Biol. 2004;24(5):1884–96.CrossRefPubMedPubMedCentral
21.
Wang Y, Dai DL, Martinka M, Li G. Prognostic significance of nuclear ING3 expression in human cutaneous melanoma. Clin Cancer Res. 2007;13(14):4111–6.CrossRefPubMed
22.
Gunduz M, Beder LB, Gunduz E, Nagatsuka H, Fukushima K, Pehlivan D, Cetin E, Yamanaka N, Nishizaki K, Shimizu K, et al. Downregulation of ING3 mRNA expression predicts poor prognosis in head and neck cancer. Cancer Sci. 2008;99(3):531–8.CrossRefPubMed
23.
Wang J, Liu Z, Feng X, Gao S, Xu S, Liu P. Tumor suppressor gene ING3 induces cardiomyocyte hypertrophy via inhibition of AMPK and activation of p38 MAPK signaling. Arch Biochem Biophys. 2014;562:22–30.CrossRefPubMed
24.
Nabbi A, Almami A, Thakur S, Suzuki K, Boland D, Bismar TA, Riabowol K. ING3 protein expression profiling in normal human tissues suggest its role in cellular growth and self-renewal. Eur J Cell Biol. 2015;94(5):214–22.CrossRefPubMed
25.
Almami A, Hegazy SA, Nabbi A, Alshalalfa M, Salman A, Abou-Ouf H, Riabowol K, Bismar TA. ING3 is associated with increased cell invasion and lethal outcome in ERG-negative prostate cancer patients. Tumour Biol. 2016;37(7):9731–8.CrossRefPubMed
26.
Bismar TA, Alshalalfa M, Petersen LF, Teng LH, Gerke T, Bakkar A, Al-Mami A, Liu S, Dolph M, Mucci LA, et al. Interrogation of ERG gene rearrangements in prostate cancer identifies a prognostic 10-gene signature with relevant implication to patients' clinical outcome. BJU Int. 2014;113(2):309–19.CrossRefPubMed
27.
Meerbrey KL, Hu G, Kessler JD, Roarty K, Li MZ, Fang JE, Herschkowitz JI, Burrows AE, Ciccia A, Sun T, et al. The pINDUCER lentiviral toolkit for inducible RNA interference in vitro and in vivo. Proc Natl Acad Sci U S A. 2011;108(9):3665–70.CrossRefPubMedPubMedCentral
28.
Saeed K, Ostling P, Bjorkman M, Mirtti T, Alanen K, Vesterinen T, Sankila A, Lundin J, Lundin M, Rannikko A, et al. Androgen receptor-interacting protein HSPBAP1 facilitates growth of prostate cancer cells in androgen-deficient conditions. Int J Cancer. 2015;136(11):2535–45.CrossRefPubMed
29.
Cancer Genome Atlas Research Network. The molecular taxonomy of primary prostate cancer. Cell. 2015;163(4):1011–25.CrossRef
30.
Jin HJ, Kim J, Yu J. Androgen receptor genomic regulation. Transl Androl Urol. 2013;2(3):157–77.PubMed
31.
Wu HC, Hsieh JT, Gleave ME, Brown NM, Pathak S, Chung LW. Derivation of androgen-independent human LNCaP prostatic cancer cell sublines: role of bone stromal cells. Int J Cancer. 1994;57(3):406–12.CrossRefPubMed
32.
Thalmann GN, Anezinis PE, Chang SM, Zhau HE, Kim EE, Hopwood VL, Pathak S, von Eschenbach AC, Chung LW. Androgen-independent cancer progression and bone metastasis in the LNCaP model of human prostate cancer. Cancer Res. 1994;54(10):2577–81.PubMed
33.
Lai JS, Herr W. Ethidium bromide provides a simple tool for identifying genuine DNA-independent protein associations. Proc Natl Acad Sci U S A. 1992;89(15):6958–62.CrossRefPubMedPubMedCentral
34.
35.
Jaaskelainen T, Makkonen H, Palvimo JJ. Steroid up-regulation of FKBP51 and its role in hormone signaling. Curr Opin Pharmacol. 2011;11(4):326–31.CrossRefPubMed
36.
Snoek R, Rennie PS, Kasper S, Matusik RJ, Bruchovsky N. Induction of cell-free, in vitro transcription by recombinant androgen receptor peptides. J Steroid Biochem Mol Biol. 1996;59(3-4):243–50.CrossRefPubMed
37.
Shiota M, Yokomizo A, Masubuchi D, Tada Y, Inokuchi J, Eto M, Uchiumi T, Fujimoto N, Naito S. Tip60 promotes prostate cancer cell proliferation by translocation of androgen receptor into the nucleus. Prostate. 2010;70(5):540–54.PubMed
38.
Katz MH. Multivariable analysis: a practical guide for clinicians and public health researchers. New York: Cambridge University Press; 2011.CrossRef
39.
Cox DR. Regression models and life tables. J R Stat Soc. 1972;34:187–220.
40.
Memarzadeh S, Cai H, Janzen DM, Xin L, Lukacs R, Riedinger M, Zong Y, DeGendt K, Verhoeven G, Huang J, et al. Role of autonomous androgen receptor signaling in prostate cancer initiation is dichotomous and depends on the oncogenic signal. Proc Natl Acad Sci U S A. 2011;108(19):7962–7.CrossRefPubMedPubMedCentral
41.
Cai H, Babic I, Wei X, Huang J, Witte ON. Invasive prostate carcinoma driven by c-Src and androgen receptor synergy. Cancer Res. 2011;71(3):862–72.CrossRefPubMed
42.
Shi X, Hong T, Walter KL, Ewalt M, Michishita E, Hung T, Carney D, Pena P, Lan F, Kaadige MR, et al. ING2 PHD domain links histone H3 lysine 4 methylation to active gene repression. Nature. 2006;442(7098):96–9.PubMedPubMedCentral
43.
Eapen SA, Netherton SJ, Sarker KP, Deng L, Chan A, Riabowol K, Bonni S. Identification of a novel function for the chromatin remodeling protein ING2 in muscle differentiation. PLoS One. 2012;7(7), e40684.CrossRefPubMedPubMedCentral
44.
Berger PL, Frank SB, Schulz VV, Nollet EA, Edick MJ, Holly B, Chang TT, Hostetter G, Kim S, Miranti CK. Transient induction of ING4 by Myc drives prostate epithelial cell differentiation and its disruption drives prostate tumorigenesis. Cancer Res. 2014;74(12):3357–68.CrossRefPubMedPubMedCentral
45.
Vieyra D, Senger DL, Toyama T, Muzik H, Brasher PM, Johnston RN, Riabowol K, Forsyth PA: Altered subcellular localization and low frequency of mutations of ING1 in human brain tumors. Clin Cancer Res. 2003;9(16 Pt 1):5952-5961.
46.
W. Gong, M. Russell, K. Suzuki, K. Riabowol. Subcellular Targeting of p33ING1b by Phosphorylation-Dependent 14-3-3 Binding Regulates p21WAF1 Expression. Molecular and Cellular Biology. 2006;26(8):2947-2954
47.
Kim S, Natesan S, Cornilescu G, Carlson S, Tonelli M, McClurg UL, Binda O, Robson CN, Markley JL, Balaz S, et al. Mechanism of Histone H3K4me3 Recognition by the Plant Homeodomain of Inhibitor of Growth 3. 2016;291(35):18326-41.
48.
Esmaeili M, Jennek S, Ludwig S, Klitzsch A, Kraft F, Melle C, Baniahmad A. The tumor suppressor ING1b is a novel corepressor for the androgen receptor and induces cellular senescence in prostate cancer cells. J Mol Cell Biol. 2016;8(3):207–20.CrossRefPubMed
49.
Li L, Lou Z, Wang L. The role of FKBP5 in cancer aetiology and chemoresistance. Br J Cancer. 2011;104(1):19–23.CrossRefPubMed
50.
Ni L, Yang CS, Gioeli D, Frierson H, Toft DO, Paschal BM. FKBP51 promotes assembly of the Hsp90 chaperone complex and regulates androgen receptor signaling in prostate cancer cells. Mol Cell Biol. 2010;30(5):1243–53.CrossRefPubMedPubMedCentral
51.
Periyasamy S, Hinds Jr T, Shemshedini L, Shou W, Sanchez ER. FKBP51 and Cyp40 are positive regulators of androgen-dependent prostate cancer cell growth and the targets of FK506 and cyclosporin A. Oncogene. 2010;29(11):1691–701.CrossRefPubMed
52.
Yu Z, Chen S, Sowalsky AG, Voznesensky OS, Mostaghel EA, Nelson PS, Cai C, Balk SP. Rapid induction of androgen receptor splice variants by androgen deprivation in prostate cancer. Clin Cancer Res. 2014;20(6):1590–600.CrossRefPubMedPubMedCentral
53.
Sapountzi V, Logan IR, Robson CN. Cellular functions of TIP60. Int J Biochem Cell Biol. 2006;38(9):1496–509.CrossRefPubMed
54.
Yang HY, Liu HL, Tian LT, Song RP, Song X, Yin DL, Liang YJ, Qu LD, Jiang HC, Liu JR, et al. Expression and prognostic value of ING3 in human primary hepatocellular carcinoma. Exp Biol Med (Maywood). 2012;237(4):352–61.CrossRef
55.
Yu G, Lee YC, Cheng CJ, Wu CF, Song JH, Gallick GE, Yu-Lee LY, Kuang J, Lin SH. RSK promotes prostate cancer progression in bone through ING3, CKAP2, and PTK6-mediated cell survival. Mol Cancer Res. 2015;13(2):348–57.CrossRefPubMed
56.
Zhu ML, Kyprianou N. Role of androgens and the androgen receptor in epithelial-mesenchymal transition and invasion of prostate cancer cells. FASEB J. 2010;24(3):769–77.CrossRefPubMedPubMedCentral
57.
Yu J, Yu J, Mani RS, Cao Q, Brenner CJ, Cao X, Wang X, Wu L, Li J, Hu M, et al. An integrated network of androgen receptor, polycomb, and TMPRSS2-ERG gene fusions in prostate cancer progression. Cancer Cell. 2010;17(5):443–54.CrossRefPubMedPubMedCentral
Metadata
Title
ING3 promotes prostate cancer growth by activating the androgen receptor
Authors
Arash Nabbi
Urszula L. McClurg
Subhash Thalappilly
Amal Almami
Mahsa Mobahat
Tarek A. Bismar
Olivier Binda
Karl T. Riabowol
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Medicine / Issue 1/2017
Electronic ISSN: 1741-7015
DOI
https://doi.org/10.1186/s12916-017-0854-0

Other articles of this Issue 1/2017

BMC Medicine 1/2017 Go to the issue

Research article

Preoperative optimization of patient expectations improves long-term outcome in heart surgery patients: results of the randomized controlled PSY-HEART trial

Research article

Daily home fortification with iron as ferrous fumarate versus NaFeEDTA: a randomised, placebo-controlled, non-inferiority trial in Kenyan children

Commentary

Humanitarian and primary healthcare needs of refugee women and children in Afghanistan

Opinion

Gestational diabetes mellitus—right person, right treatment, right time?

Research article

Impact of ischemic preconditioning on surgical treatment of brain tumors: a single-center, randomized, double-blind, controlled trial

Research article

Exposure to bacterial products lipopolysaccharide and flagellin and hepatocellular carcinoma: a nested case-control study