title: Lysosome-dependent p300/FOXP3 degradation and limits Treg cell functions and enhances targeted therapy against cancers.
abstract: p300 is one of several acetyltransferases that regulate FOXP3 acetylation and functions. Our recent studies have defined a complex set of histone acetyltransferase interactions which can lead to enhanced or repressed changes in FOXP3 function. We have explored the use of a natural p300 inhibitor, Garcinol, as a tool to understand mechanisms by which p300 regulates FOXP3 acetylation. In the presence of Garcinol, p300 appears to become disassociated from the FOXP3 complex and undergoes lysosome-dependent degradation. As a consequence of p300's physical absence, FOXP3 becomes less acetylated and eventually degraded, a process that cannot be rescued by the proteasome inhibitor MG132. p300 plays a complex role in FOXP3 acetylation, as it could also acetylate a subset of four Lys residues that repressively regulate total FOXP3 acetylation. Garcinol acts as a degradation device to reduce the suppressive activity of regulatory T cells (Treg) and to enhance the in vivo anti-tumor activity of a targeted therapeutic anti-p185(her2/neu) (ERBB2) antibody in MMTV-neu transgenics implanted with neu transformed breast tumor cells. Our studies provide the rationale for molecules that disrupt p300 stability to limit Treg functions in targeted therapies for cancers.
authors: Department of Pathology and Lab Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104-6082, USA.
authors: Taofeng
authors: T
authors: Du
authors: Yasuhiro
authors: Y
authors: Nagai
authors: Yan
authors: Y
authors: Xiao
authors: Mark I
authors: MI
authors: Greene
authors: Hongtao
authors: H
authors: Zhang
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002460:Cell Line; D002738:Chloroquine / Q000494:pharmacology; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D051548:Histone Acetyltransferases / Q000037:antagonists & inhibitors; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D058990:Molecular Targeted Therapy / Q000379:methods; D009154:Mutation; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D013729:Terpenes / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D013729:Terpenes; D002738:Chloroquine; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; D000074443:Lysine Acetyltransferase 5; C054597:garcinol
keywords: Acetyltransferase; FOXP3; Garcinol; Lysosome degradation; Regulatory T cells; T(reg); p300
references: Curr Opin Immunol. 2011 Oct;23(5):670-8
references: 21798734
references: Gastroenterology. 2010 Feb;138(2):583-94
references: 19879272
references: Nature. 1984 Dec 6-12;312(5994):545-8
references: 6504162
references: Cell Cycle. 2007 Jun 15;6(12):1432-6
references: 17592252
references: J Clin Invest. 2005 Nov;115(11):3276-84
references: 16211090
references: Blood. 2010 Feb 4;115(5):965-74
references: 19996091
references: Cancer Cell. 2010 Aug 9;18(2):160-70
references: 20708157
references: Chem Biol. 2007 Jun;14(6):645-57
references: 17584612
references: J Clin Oncol. 2009 Apr 10;27(11):1746-52
references: 19255331
references: Proc Natl Acad Sci U S A. 2008 Oct 21;105(42):16254-9
references: 18838682
references: Proc Natl Acad Sci U S A. 1986 Dec;83(23):9129-33
references: 3466178
references: J Immunol. 2012 Mar 15;188(6):2712-21
references: 22312127
references: Epigenetics. 2011 Aug;6(8):957-61
references: 21730760
references: Oncogene. 2003 Jun 19;22(25):3927-36
references: 12813466
references: Nat Med. 1995 Jul;1(7):644-8
references: 7585144
references: Exp Mol Pathol. 1999 Sep;67(1):15-25
references: 10493889
references: Cell Rep. 2012 Jun 28;1(6):665-75
references: 22813742
references: J Immunol. 2017 Feb 1;198(3):981-985
references: 28115586
references: Mol Cell Biol. 2011 May;31(10):2066-78
references: 21444725
references: Nat Immunol. 2007 Mar;8(3):277-84
references: 17220892
references: Oncogene. 2006 Dec 14;25(59):7740-6
references: 16785990
references: Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7142-7
references: 21482773
references: J Oncol. 2012;2012:647206
references: 22745638
references: Nature. 2007 Feb 15;445(7129):766-70
references: 17220876
references: Breast Cancer Res Treat. 2012 Aug;135(1):103-14
references: 22562121
references: J Phys Chem B. 2007 Oct 18;111(41):11877-9
references: 17894486
references: J Hematol Oncol. 2009 Sep 02;2:38
references: 19725977
references: J Biol Chem. 2004 Aug 6;279(32):33716-26
references: 15155757
references: Mol Cell Biol. 2005 Apr;25(7):2673-87
references: 15767673
references: Cancer Res. 2013 Apr 15;73(8):2619-27
references: 23396586
references: Annu Rev Immunol. 2006;24:209-26
references: 16551248
references: Cancer Res. 2012 Jul 1;72(13):3125-30
references: 22721837
references: Curr Opin Immunol. 2010 Oct;22(5):583-91
references: 20869864
references: Exp Mol Pathol. 2009 Oct;87(2):99-104
references: 19577564
references: Immunol Cell Biol. 2012 Jan;90(1):95-100
references: 22124370
references: Mol Cancer Ther. 2012 Oct;11(10):2193-201
references: 22821148
references: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4571-6
references: 17360565
references: Proc Natl Acad Sci U S A. 2008 Sep 16;105(37):14023-7
references: 18779564