E3 ligase UHRF2 stabilizes the acetyltransferase TIP60 and regulates H3K9ac and H3K14ac via RING finger domain

Abstract

UHRF2 is a ubiquitin-protein ligase E3 that regulates cell cycle, genomic stability and epigenetics. We conducted a co-immunoprecipitation assay and found that TIP60 and HDAC1 interact with UHRF2. We previously demonstrated that UHRF2 regulated H3K9ac and H3K14ac differentially in normal and cancer cells. However, the accurate signal transduction mechanisms were not clear. In this study, we found that TIP60 acted downstream of UHRF2 to regulate H3K9ac and H3K14ac expression. TIP60 is stabilized in normal cells by UHRF2 ubiquitination. However, TIP60 is destabilized in cancer cells. Depletion or inhibition of TIP60 disrupts the regulatory relationship between UHRF2, H3K9ac and H3K14ac. In summary, the findings suggest that UHRF2 mediated the post-translational modification of histones and the initiation and progression of cancer.

Key words： UHRF2; TIP60; ubiquitination; acetylation; hepatocellular carcinoma

References

1 Achour M, Fuhrmann G, Alhosin M, Ronde P, Chataigneau T, Mousli M, Schini-Kerth VB, Bronner C (2009) UHRF1 recruits the histone acetyltransferase Tip60 and controls its expression and activity. Biochem Biophys Res Commun 390:523–528

2 Arnaudo AM, Garcia BA (2013) Proteomic characterization of novel histonepost-translational modifications. Epigenetics Chromatin 6:24

3 Bassi C, Li YT, Khu K, Mateo F, Baniasadi PS, Elia A, Mason J, Stambolic V, Pujana MA, Mak TW, Gorrini C (2016) The acetyltransferase Tip60 contributes to mammary tumorigenesis by modulating DNA repair. Cell Death Differ 23:1198–1208

4 Basu A, Rose KL, Zhang J, Beavis RC, Ueberheide B, Garcia BA, Chait B, Zhao Y, Hunt DF, Segal E, Allis CD, Hake SB (2009) Proteome-wide prediction of acetylation substrates. Proc Natl Acad Sci USA 106:13785–13790

5 Bhaumik SR, Smith E, Shilatifard A (2007) Covalent modifications of histones during development and disease pathogenesis. Nat Struct Mol Biol 14:1008–1016

6 Bronner C, Achour M, Arima Y, Chataigneau T, Saya H, Schini-Kerth VB (2007) The UHRF family: oncogenes that are drugable targets for cancer therapy in the near future? Pharmacol Ther 115:419–434

7 Dai C, Shi D, Gu W (2013) Negative regulation of the acetyltransferase TIP60-p53 interplay by UHRF1 (ubiquitin-like with PHD and RING finger domains 1). J Biol Chem 288:19581–19592

8 Das TP, Suman S, Papu John AM, Pal D, Edwards A, Alatassi H, Ankem MK, Damodaran C (2016) Activation of AKT negatively regulates the pro-apoptotic function of death-associated protein kinase 3 (DAPK3) in prostate cancer. Cancer Lett 377:134–139

9 Feng YL, Xiang JF, Kong N, Cai XJ, Xie AY (2016) Buried territories: heterochromatic response to DNA double-strand breaks. Acta Biochim Biophys Sin 48:594–602

10 Grezy A, Chevillard-Briet M, Trouche D, Escaffit F (2016) Control of genetic stability by a new heterochromatin compaction pathway involving the Tip60 histone acetyltransferase. Mol Biol Cell 27:599–607

11 Harrison JS, Jacobs TM, Houlihan K, Van Doorslaer K, Kuhlman B (2016) UbSRD: the ubiquitin structural relational database. J Mol Biol 428:679–687

12 Hershko A, Ciechanover A, Varshavsky A (2000) The ubiquitin system. Nat Am 10:1073–1081

13 Holt MT, David Y, Pollock S, Tang Z, Jeon J, Kim J, Roeder RG, Muir TW (2015) Identification of a functional hotspot on ubiquitin required for stimulation of methyltransferase activity on chromatin. Proc Natl Acad Sci USA 112:10365–10370

14 Ikura M, Furuya K, Matsuda S, Matsuda R, Shima H, Adachi J, Matsuda T, Shiraki T, Ikura T (2015) Acetylation of histone H2AX at Lys 5 by the TIP60 histone acetyltransferase complex is essential for the dynamic binding of NBS1 to damaged chromatin. Mol Cell Biol 35:4147–4157

15 Jacquet K, Fradet-Turcotte A, Avvakumov N, Lambert JP, Roques C, Pandita RK, Paquet E, Herst P, Gingras AC, Pandita TK, Legube G, Doyon Y, Durocher D, Cote J (2016) The TIP60 complex regulates bivalent chromatin recognition by 53BP1 through direct H4K20me binding and H2AK15 acetylation. Mol Cell 62:409–421

16 Jang SM, Kim JW, Kim CH, An JH, Johnson A, Song PI, Rhee S, Choi KH (2015) KAT5-mediated SOX4 acetylation orchestrates chromatin remodeling during myoblast differentiation. Cell Death Dis 6:e1857

17 Karmodiya K, Krebs A, Mustapha OS, Kimura H, Tora L (2012) H3K9 and H3K14 acetylation co-occur atmany gene regulatory elements, while H3K14ac marks a subset of inactive inducible promoters in mouse embryonic stemcells. BMC Genom 424:1471–2164

18 Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693–705

19 Lechtenberg BC, Rajput A, Sanishvili R, Dobaczewska MK, Ware CF, Mace PD, Riedl SJ (2016) Structure of a HOIP/E2∼ubiquitin complex reveals RBR E3 ligase mechanism and regulation. Nature 529:546–550

20 Leithe E (2016) Regulation of connexins by the ubiquitin system: implications for intercellular communication and cancer. Biochim Biophys Acta 1865:133–146

21 Li E (2002) Chromatin modification and epigenetic reprogramming in mammalian development. Nat Rev Genetics 3:662–673

22 Li Y, Mori T, Hata H, Homma Y, Kochi H (2004) NIRF induces G1 arrest and associates with Cdk2. Biochem Biophys Res Commun 319:464–468

23 Liang BQ, Li DH, Hui HL, Hai YL, Xiao YL, Yong BY (2016) Cataractcausing mutation S228P promotes βB1-crystallin aggregation and degradation by separating two interacting loops in C-terminal domain. Protein Cell 7:501–515

24 Mo F, Zhuang X, Liu X, Yao PY, Qin B, Su Z, Zang J, Wang Z, Zhang J, Dou Z, Tian C, Teng M, Niu L, Hill DL, Fang G, Ding X, Fu C, Yao X (2016) Acetylation of Aurora B by TIP60 ensures accurate chromosomal segregation. Nat Chem Biol 12:226–232

25 Mori T, Li Y, Hata H, Kochi H (2004) NIRF is a ubiquitin ligase that is capable of ubiquitinating PCNP, a PEST-containing nuclear protein. FEBS Lett 557:209–214

26 Mori T, Ikeda DD, Fukushima T, Takenoshita S, Kochi H (2011) NIRF constitutes a nodal point in the cell cycle network and is a candidate tumor suppressor. Cell Cycle 10:3284–3299

27 Pichler G, Wolf P, Schmidt CS, Meilinger D, Schneider K, Frauer C, Fellinger K, Rottach A, Leonhardt H (2011) Cooperative DNA and histone binding by Uhrf2 links the two major repressive epigenetic pathways. J Cell Biochem 112:2585–2593

28 Pokholok DK, Harbison CT, Levine S, Cole M, Hannett NM, Lee TI, Bell GW, Walker K, Rolfe PA, Herbolsheimer E, Zeitlinger J, Lewitter F, Gifford DK, Young RA (2005) Genome-wide map of nucleosome acetylation and methylation in yeast. Cell 122:517–527

29 Qian G, Jin F, Chang L, Yang Y, Peng H, Duan C (2012) NIRF, a novel ubiquitin ligase, interacts with hepatitis B virus core protein and promotes its degradation. Biotechnol Lett 34:29–36

30 Renaud E, Barascu A, Rosselli F (2016) Impaired TIP60-mediated H4K16 acetylation accounts for the aberrant chromatin accumulation of 53BP1 and RAP80 in Fanconi anemia pathway-deficient cells. Nucl Acids Res 44:648–656

31 Su J, Wang F, Cai Y, Jin J (2016) The functional analysis of histone acetyltransferase MOF in tumorigenesis. Int J Mol Sci. doi:10. 3390/ijms17010099

32 Sun Y, Sun J, Lungchukiet P, Quarni W, Yang S, Zhang X, Bai W (2015) Fe65 suppresses breast cancer cell migration and invasion through Tip60 mediated cortactin acetylation. Sci Rep 5:11529

33 Takase N, Koma YI, Urakawa N, Nishio M, Arai N, Akiyama H, Shigeoka M, Kakeji Y, Yokozaki H (2016) NCAM- and FGF-2-mediated FGFR1 signaling in the tumor microenvironment of esophageal cancer regulates the survival and migration of tumorassociated macrophages and cancer cells. Cancer Lett 380:47–58

34 Tan M, Luo H, Lee S, Jin F, Yang JS, Montellier E, Buchou T, Cheng Z, Rousseaux S, Rajagopal N, Lu Z, Ye Z, Zhu Q, Wysocka J, Ye Y, Khochbin S, Ren B, Zhao Y (2011) Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146:1016–1028

35 Vinther-Jensen T, Simonsen AH, Budtz-Jorgensen E, Hjermind LE, Nielsen JE (2015) Ubiquitin: a potential cerebrospinal fluid progression marker in Huntington’s disease. Eur J Neurol 22:1378–1384

36 Wang Z, Zang C, Rosenfeld JA, Schones DE, Barski A, Cuddapah S, Cui K, Roh TY, Peng W, Zhang MQ, Zhao K (2008) Combinatorial patterns of histone acetylations and methylations in the human genome. Nat Genetics 40:897–903

37 Wang F, Zhang P, Ma Y, Yang J, Moyer MP, Shi C, Peng J, Qin H (2012) NIRF is frequently upregulated in colorectal cancer and its oncogenicity can be suppressed by let-7a microRNA. Cancer Lett 314:223–231

38 Yamada S, Ohta K, Yamada T (2013) Acetylated histone H3K9 is associated with meiotic recombination hotspots, and plays a role in recombination redundantly with other factors including the H3K4 methylase Set1 in fission yeast. Nucl Acids Res 41:3504–3517

39 Yamano K, Queliconi BB, Koyano F, Saeki Y, Hirokawa T, Tanaka K, Matsuda N (2015) Site-specific interaction mapping of phosphorylated ubiquitin to uncover parkin activation. J Biol Chem 290:25199–25211