title: Ferritin H induction by histone deacetylase inhibitors.
abstract: Because both iron deficiency and iron excess are deleterious to normal cell function, the intracellular level of iron must be tightly controlled. Ferritin, an iron binding protein, regulates iron balance by storing iron in a bioavailable but nontoxic form. Ferritin protein comprises two subunits: ferritin H, which contains ferroxidase activity, and ferritin L. Here we demonstrate that ferritin H mRNA and protein are induced by histone deacetylase inhibitors (HDAC inhibitors), a promising class of anti-cancer drugs, in cultured human cancer cells. Deletion analysis and EMSA assays reveal that the induction of ferritin H occurs at a transcriptional level via Sp1 and NF-Y binding sites near the transcriptional start site of the human ferritin H promoter. Classically, HDAC inhibitors modulate gene expression by increasing histone acetylation. However, ChIP assays demonstrate that HDAC inhibitors induce ferritin H transcription by increasing NF-Y binding to the ferritin H promoter without changes in histone acetylation. These results identify ferritin H as a new target of HDAC inhibitors, and recruitment of NF-Y as a novel mechanism of action of HDAC inhibitors.
authors.affiliation: Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Xiumin
authors.initials: X
authors.lastname: Di
authors.forename: Suzy V
authors.initials: SV
authors.lastname: Torti
authors.forename: Frank M
authors.initials: FM
authors.lastname: Torti
mesh_terms: D001052:Apoferritins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D014407:Tumor Cells, Cultured
chemical_list: D056572:Histone Deacetylase Inhibitors; D012333:RNA, Messenger; D001052:Apoferritins
references.citation: Free Radic Biol Med. 2006 Apr 1;40(7):1152-60
references.pmid: 16545682
references.citation: Proc Natl Acad Sci U S A. 1989 Dec;86(24):9774-7
references.pmid: 2481317
references.citation: J Biol Chem. 1999 Mar 19;274(12):7623-6
references.pmid: 10075648
references.citation: Mol Biol Cell. 2008 Dec;19(12):5203-13
references.pmid: 18815279
references.citation: Cancer Res. 1999 Sep 1;59(17):4392-9
references.pmid: 10485488
references.citation: Mol Cell Biol. 1999 Aug;19(8):5504-11
references.pmid: 10409740
references.citation: J Biol Chem. 1997 Aug 15;272(33):20736-41
references.pmid: 9252395
references.citation: J Biol Chem. 2005 Nov 18;280(46):38879-87
references.pmid: 16186112
references.citation: Oncogene. 2003 Oct 30;22(49):7762-73
references.pmid: 14586402
references.citation: Cancer Res. 2003 May 15;63(10):2624-30
references.pmid: 12750289
references.citation: Ann N Y Acad Sci. 1999;886:195-9
references.pmid: 10667218
references.citation: J Biol Chem. 2002 May 10;277(19):16823-30
references.pmid: 11877441
references.citation: Cell. 2004 Sep 17;118(6):781-94
references.pmid: 15369676
references.citation: J Biol Chem. 1999 Mar 12;274(11):7501-7
references.pmid: 10066817
references.citation: Mol Cell Biol. 2003 Jul;23(14):4841-58
references.pmid: 12832471
references.citation: Mol Cell Biol. 1997 Mar;17(3):1387-95
references.pmid: 9032265
references.citation: Int J Cancer. 2004 Nov 1;112(2):171-8
references.pmid: 15352027
references.citation: Nat Rev Cancer. 2006 Jan;6(1):38-51
references.pmid: 16397526
references.citation: J Biol Chem. 2000 Feb 4;275(5):3021-4
references.pmid: 10652280
references.citation: J Biol Chem. 2005 Apr 22;280(16):16467-75
references.pmid: 15722551
references.citation: Nature. 1997 Sep 25;389(6649):349-52
references.pmid: 9311776
references.citation: J Biol Chem. 2002 Sep 27;277(39):35783-6
references.pmid: 12176973
references.citation: J Natl Cancer Inst. 2000 Aug 2;92(15):1210-6
references.pmid: 10922406
references.citation: J Biol Chem. 2003 Mar 7;278(10):8385-94
references.pmid: 12511565
references.citation: J Immunol. 2000 Oct 1;165(7):3907-16
references.pmid: 11034398
references.citation: Gene. 1992 Feb 15;111(2):255-60
references.pmid: 1541403
references.citation: Biochem Pharmacol. 2004 Sep 15;68(6):1221-9
references.pmid: 15313420
references.citation: Blood. 2002 May 15;99(10):3505-16
references.pmid: 11986201
references.citation: Blood. 1996 Mar 1;87(5):2057-64
references.pmid: 8634457
references.citation: Nat Rev Cancer. 2001 Dec;1(3):194-202
references.pmid: 11902574
references.citation: Clin Transl Oncol. 2008 Jul;10(7):395-8
references.pmid: 18628067
references.citation: J Biol Chem. 2007 Aug 24;282(34):24650-9
references.pmid: 17604281
references.citation: Proc Natl Acad Sci U S A. 2005 Jan 18;102(3):673-8
references.pmid: 15637150
references.citation: Oncogene. 2004 Jul 8;23(31):5340-9
references.pmid: 15107822
references.citation: Cancer Cell. 2003 Jul;4(1):13-8
references.pmid: 12892709
references.citation: FEBS Lett. 2004 Jul 16;570(1-3):37-40
references.pmid: 15251435
references.citation: Cell. 2004 Apr 30;117(3):285-97
references.pmid: 15109490
references.citation: Biochim Biophys Acta. 2007 Oct;1771(10):1271-82
references.pmid: 17894944
references.citation: J Biol Chem. 2003 Jan 24;278(4):2361-9
references.pmid: 12435735
references.citation: J Biol Chem. 2002 Jul 12;277(28):25568-75
references.pmid: 11980894
references.citation: Biochem J. 2001 Jul 1;357(Pt 1):241-7
references.pmid: 11415455
references.citation: J Biol Chem. 2000 Aug 18;275(33):25122-9
references.pmid: 10833524
references.citation: J Cell Biochem. 2005 Oct 1;96(2):293-304
references.pmid: 16088937
references.citation: Biochem Biophys Res Commun. 2003 Dec 26;312(4):950-7
references.pmid: 14651963
references.citation: J Biol Chem. 2002 Oct 11;277(41):38230-8
references.pmid: 12151407
references.citation: Mol Cell Biol. 2004 Jun;24(12):5106-18
references.pmid: 15169878
references.citation: Mol Cell Biol. 1998 Jul;18(7):4377-84
references.pmid: 9632821
references.citation: J Biol Chem. 2008 Dec 5;283(49):33911-8
references.pmid: 18819919