title: Nuclear localization of CD26 induced by a humanized monoclonal antibody inhibits tumor cell growth by modulating of POLR2A transcription.
abstract: CD26 is a type II glycoprotein known as dipeptidyl peptidase IV and has been identified as one of the cell surface markers associated with various types of cancers and a subset of cancer stem cells. Recent studies have suggested that CD26 expression is involved in tumor growth, tumor invasion, and metastasis. The CD26 is shown in an extensive intracellular distribution, ranging from the cell surface to the nucleus. We have previously showed that the humanized anti-CD26 monoclonal antibody (mAb), YS110, exhibits inhibitory effects on various cancers. However, functions of CD26 on cancer cells and molecular mechanisms of impaired tumor growth by YS110 treatment are not well understood. In this study, we demonstrated that the treatment with YS110 induced nuclear translocation of both cell-surface CD26 and YS110 in cancer cells and xenografted tumor. It was shown that the CD26 and YS110 were co-localized in nucleus by immunoelectron microscopic analysis. In response to YS110 treatment, CD26 was translocated into the nucleus via caveolin-dependent endocytosis. It was revealed that the nuclear CD26 interacted with a genomic flanking region of the gene for POLR2A, a subunit of RNA polymerase II, using a chromatin immunoprecipitation assay. This interaction with nuclear CD26 and POLR2A gene consequently led to transcriptional repression of the POLR2A gene, resulting in retarded cell proliferation of cancer cells. Furthermore, the impaired nuclear transport of CD26 by treatment with an endocytosis inhibitor or expressions of deletion mutants of CD26 reversed the POLR2A repression induced by YS110 treatment. These findings reveal that the nuclear CD26 functions in the regulation of gene expression and tumor growth, and provide a novel mechanism of mAb-therapy related to inducible translocation of cell-surface target molecule into the nucleus.
authors: Department of Pathology, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors: Kohji
authors: K
authors: Yamada
authors: Mutsumi
authors: M
authors: Hayashi
authors: Hiroko
authors: H
authors: Madokoro
authors: Hiroko
authors: H
authors: Nishida
authors: Wenlin
authors: W
authors: Du
authors: Kei
authors: K
authors: Ohnuma
authors: Michiie
authors: M
authors: Sakamoto
authors: Chikao
authors: C
authors: Morimoto
authors: Taketo
authors: T
authors: Yamada
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D018819:Dipeptidyl Peptidase 4 / Q000276:immunology* / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D012319:RNA Polymerase II / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D012319:RNA Polymerase II; D018819:Dipeptidyl Peptidase 4
references: Cancer Cell. 2004 Sep;6(3):251-61
references: 15380516
references: Semin Oncol. 1999 Aug;26(4 Suppl 12):60-70
references: 10482195
references: N Engl J Med. 2001 Jul 26;345(4):241-7
references: 11474661
references: J Biol Chem. 2006 Jul 7;281(27):18878-87
references: 16644731
references: Clin Cancer Res. 2001 Jul;7(7):2031-40
references: 11448921
references: Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3470-7
references: 16740772
references: J Biol Chem. 2004 Mar 26;279(13):12565-73
references: 14707142
references: J Biol Chem. 2007 May 25;282(21):15645-51
references: 17363367
references: Cell Stem Cell. 2010 Jun 4;6(6):603-15
references: 20569697
references: Clin Cancer Res. 2012 Mar 1;18(5):1447-56
references: 22261805
references: Hepatology. 1991 Jan;13(1):15-20
references: 1988335
references: Int J Exp Pathol. 1992 Apr;73(2):215-22
references: 1349235
references: Nat Struct Biol. 2003 Jan;10(1):19-25
references: 12483204
references: Clin Cancer Res. 2007 Jul 15;13(14):4191-200
references: 17634548
references: Oncogene. 2010 Jul 15;29(28):3997-4006
references: 20473332
references: Nat Rev Mol Cell Biol. 2011 Jul 22;12(8):517-33
references: 21779028
references: Cell. 2012 Mar 16;148(6):1081-4
references: 22424219
references: J Biol Chem. 2005 May 13;280(19):19166-76
references: 15753095
references: Cancer Cell Int. 2009 Jun 26;9:17
references: 19555512
references: J Clin Oncol. 2003 Nov 1;21(21):3940-7
references: 12975461
references: Proc Natl Acad Sci U S A. 2004 Aug 24;101(34):12736-41
references: 15310851
references: J Cell Biol. 2001 Nov 26;155(5):755-62
references: 11714729
references: Immunology. 2002 Nov;107(3):325-33
references: 12423308
references: Genomics. 2010 Apr;95(4):210-6
references: 20153416
references: Blood. 1999 Jun 1;93(11):3678-84
references: 10339474
references: J Cell Biochem. 2006 Aug 15;98(6):1570-83
references: 16552725
references: Onco Targets Ther. 2011 Apr 08;4:27-32
references: 21552413
references: Biochim Biophys Acta. 2011 Oct;1813(10):1708-16
references: 21782856
references: Traffic. 2007 Jul;8(7):848-66
references: 17587406
references: J Cell Biol. 2000 May 15;149(4):901-14
references: 10811830
references: Clin Lymphoma. 2004 Sep;5(2):98-101
references: 15453924
references: Curr Biol. 2004 Apr 20;14(8):R314-6
references: 15084302
references: J Biol Chem. 2007 Mar 30;282(13):10117-10131
references: 17287217
references: Lancet. 2006 Nov 11;368(9548):1696-705
references: 17098089
references: Mol Cell Biol. 2005 Dec;25(24):11005-18
references: 16314522
references: Curr Opin Cell Biol. 2010 Aug;22(4):535-40
references: 20538448
references: Nat Biotechnol. 2005 Sep;23(9):1147-57
references: 16151408
references: Nucleic Acids Res. 1992 Feb 25;20(4):910
references: 1542581
references: Am J Pathol. 1992 Oct;141(4):937-47
references: 1384341
references: Nat Rev Mol Cell Biol. 2001 Feb;2(2):107-17
references: 11252952
references: Dev Cell. 2006 Aug;11(2):213-23
references: 16890161
references: Science. 1983 Aug 26;221(4613):865-7
references: 6879183
references: Cancer Gene Ther. 2009 Jun;16(6):532-8
references: 19165236
references: Clin Cancer Res. 2009 Nov 1;15(21):6484-9
references: 19861462
references: Front Biosci. 2008 Jan 01;13:1634-45
references: 17981655
references: Br J Cancer. 2002 Sep 9;87(6):600-7
references: 12237768
references: Oncol Rep. 2011 Dec;26(6):1369-75
references: 21894438
references: Arch Biochem Biophys. 1989 Jun;271(2):366-79
references: 2658809
references: Biochem Biophys Res Commun. 2011 Jan 14;404(2):735-42
references: 21163253
references: Oncogene. 1997 May 8;14(18):2201-11
references: 9174056