title: Genomic and functional characterizations of phosphodiesterase subtype 4D in human cancers.
abstract: Discovery of cancer genes through interrogation of genomic dosage is one of the major approaches in cancer research. In this study, we report that phosphodiesterase subtype 4D (PDE4D) gene was homozygously deleted in 198 cases of 5,569 primary solid tumors (3.56%), with most being internal microdeletions. Unexpectedly, the microdeletions did not result in loss of their gene products. Screening PDE4D expression in 11 different types of primary tumor samples (n = 165) with immunohistochemistry staining revealed that its protein levels were up-regulated compared with corresponding nontransformed tissues. Importantly, depletion of endogenous PDE4D with three independent shRNAs caused apoptosis and growth inhibition in multiple types of cancer cells, including breast, lung, ovary, endometrium, gastric, and melanoma, which could be rescued by reexpression of PDE4D. We further showed that antitumor events triggered by PDE4D suppression were lineage-dependently associated with Bcl-2 interacting mediator of cell death (BIM) induction and microphthalmia-associated transcription factor (MITF) down-regulation. Furthermore, ectopic expression of the PDE4D short isoform, PDE4D2, enhanced the proliferation of cancer cells both in vitro and in vivo. Moreover, treatment of cancer cells with a unique specific PDE4D inhibitor, 26B, triggered massive cell death and growth retardation. Notably, these antineoplastic effects induced by either shRNAs or small molecule occurred preferentially in cancer cells but not in nonmalignant epithelial cells. These results suggest that although targeted by genomic homozygous microdeletions, PDE4D functions as a tumor-promoting factor and represents a unique targetable enzyme of cancer cells.
authors.affiliation: Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California School of Medicine, Los Angeles, CA 90048, USA. dchlin11@gmail.com
authors.forename: De-Chen
authors.initials: DC
authors.lastname: Lin
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.forename: Ling-Wen
authors.initials: LW
authors.lastname: Ding
authors.forename: Arjun
authors.initials: A
authors.lastname: Sharma
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Liu
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
authors.forename: Jay
authors.initials: J
authors.lastname: Vadgama
authors.forename: Beth Y
authors.initials: BY
authors.lastname: Karlan
authors.forename: Jenny
authors.initials: J
authors.lastname: Lester
authors.forename: Nicole
authors.initials: N
authors.lastname: Urban
authors.forename: Michèl
authors.initials: M
authors.lastname: Schummer
authors.forename: Ngan
authors.initials: N
authors.lastname: Doan
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Said
authors.forename: Hongmao
authors.initials: H
authors.lastname: Sun
authors.forename: Martin
authors.initials: M
authors.lastname: Walsh
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: Paresma
authors.initials: P
authors.lastname: Patel
authors.forename: Dong
authors.initials: D
authors.lastname: Yin
authors.forename: Daniel
authors.initials: D
authors.lastname: Chan
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D019253:Proto-Oncogene Proteins c-bcl-2; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human
references.citation: J Biol Chem. 1992 Sep 15;267(26):18929-39
references.pmid: 1326538
references.citation: Biochemistry. 1997 Mar 11;36(10):2968-76
references.pmid: 9062127
references.citation: Pharmacol Rev. 2006 Sep;58(3):488-520
references.pmid: 16968949
references.citation: Clin Cancer Res. 2008 Dec 1;14(23):7717-25
references.pmid: 19047098
references.citation: Blood. 1998 Oct 1;92(7):2484-94
references.pmid: 9746789
references.citation: Blood. 2002 May 1;99(9):3390-7
references.pmid: 11964308
references.citation: Pharmacol Ther. 2006 Mar;109(3):366-98
references.pmid: 16102838
references.citation: Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3556-60
references.pmid: 1373503
references.citation: Prog Nucleic Acid Res Mol Biol. 2001;69:249-315
references.pmid: 11550796
references.citation: Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5330-4
references.pmid: 8202489
references.citation: Cancer Res. 1980 Jun;40(6):1858-62
references.pmid: 6245806
references.citation: Annu Rev Biochem. 2007;76:481-511
references.pmid: 17376027
references.citation: J Biol Chem. 1999 Jul 9;274(28):19677-85
references.pmid: 10391907
references.citation: Mol Ther. 2011 Feb;19(2):362-71
references.pmid: 21119619
references.citation: Clin Cancer Res. 2005 Oct 15;11(20):7234-42
references.pmid: 16243793
references.citation: Nature. 2005 Feb 17;433(7027):764-9
references.pmid: 15716956
references.citation: J Biol Chem. 2011 Sep 23;286(38):33260-7
references.pmid: 21808067
references.citation: Nature. 2010 Feb 18;463(7283):899-905
references.pmid: 20164920
references.citation: Mol Pharmacol. 2001 Nov;60(5):1100-11
references.pmid: 11641439
references.citation: Curr Top Med Chem. 2007;7(4):391-403
references.pmid: 17305581
references.citation: Cancer Discov. 2012 May;2(5):401-4
references.pmid: 22588877
references.citation: Int J Cancer. 2009 Jan 1;124(1):16-26
references.pmid: 18814281
references.citation: Chem Res Toxicol. 2000 Oct;13(10):944-8
references.pmid: 11080038
references.citation: Bioorg Med Chem Lett. 2010 Sep 15;20(18):5502-5
references.pmid: 20709547
references.citation: Nature. 2005 Jul 7;436(7047):117-22
references.pmid: 16001072
references.citation: Clin Exp Metastasis. 2000;18(7):599-604
references.pmid: 11688965
references.citation: J Biol Chem. 2000 Jun 2;275(22):16609-17
references.pmid: 10828059
references.citation: Br J Pharmacol. 2000 Oct;131(4):811-9
references.pmid: 11030732
references.citation: Cancer Res. 2009 May 15;69(10):4388-97
references.pmid: 19401450
references.citation: Oncogene. 2013 Feb 28;32(9):1121-34
references.pmid: 22525277