KLF7 promotes pancreatic cancer growth and metastasis by up-regulating ISG expression and maintaining Golgi complex integrity.

Szczegóły
Abstrakt

Tytuł:: KLF7 promotes pancreatic cancer growth and metastasis by up-regulating ISG expression and maintaining Golgi complex integrity.
Autorzy:: Gupta R; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35233.
Malvi P; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35233.
Parajuli KR; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35233.
Janostiak R; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Bugide S; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35233.
Cai G; Department of Pathology, Yale University School of Medicine, New Haven, CT 06510.
Zhu LJ; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605.; Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605.
Green MR; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; .
Wajapeyee N; Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL 35233; .
Źródło:: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jun 02; Vol. 117 (22), pp. 12341-12351. Date of Electronic Publication: 2020 May 19.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Original Publication: Washington, DC : National Academy of Sciences
MeSH Terms:: Golgi Apparatus/*metabolism
Kruppel-Like Transcription Factors/*metabolism
Pancreatic Neoplasms/*metabolism
Animals ; Cell Line, Tumor ; Cell Proliferation ; Female ; Gene Expression Regulation, Neoplastic ; Golgi Apparatus/genetics ; Humans ; Kruppel-Like Transcription Factors/genetics ; Male ; Mice ; Mice, Knockout ; Neoplasm Metastasis ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Pancreatic Neoplasms/physiopathology ; Transcription Factors/genetics ; Transcription Factors/metabolism ; Pancreatic Neoplasms
References:: F1000Res. 2017 Nov 27;6:2050. (PMID: 29225785)
Cancer Sci. 2005 Jul;96(7):387-93. (PMID: 16053509)
Cancer Res. 2009 Sep 15;69(18):7385-92. (PMID: 19723656)
Nat Rev Cancer. 2004 Jul;4(7):540-50. (PMID: 15229479)
Tumour Biol. 2017 Jun;39(6):1010428317710410. (PMID: 28639887)
PLoS Genet. 2019 Oct 7;15(10):e1008439. (PMID: 31589613)
Science. 2008 Sep 26;321(5897):1801-6. (PMID: 18772397)
Nat Rev Mol Cell Biol. 2002 Oct;3(10):789-95. (PMID: 12360195)
Cancer Discov. 2014 Oct;4(10):1168-81. (PMID: 25015643)
Physiol Rev. 2010 Oct;90(4):1337-81. (PMID: 20959618)
Am J Pathol. 2003 Apr;162(4):1151-62. (PMID: 12651607)
Nature. 1985 Feb 28-Mar 6;313(6005):745-7. (PMID: 3883191)
Nat Rev Gastroenterol Hepatol. 2019 Apr;16(4):207-220. (PMID: 30718832)
Oncogene. 2019 Mar;38(10):1717-1733. (PMID: 30353166)
Nat Med. 2018 Aug;24(8):1143-1150. (PMID: 30038220)
J Cell Sci. 2014 Dec 1;127(Pt 23):5079-92. (PMID: 25278553)
Elife. 2016 Jan 21;5:e10820. (PMID: 26796342)
Genes Dev. 2015 Feb 1;29(3):238-49. (PMID: 25644600)
Physiology (Bethesda). 2010 Apr;25(2):85-101. (PMID: 20430953)
Sci Signal. 2011 Oct 25;4(196):rs11. (PMID: 22028470)
Oncol Lett. 2017 Apr;13(4):2281-2289. (PMID: 28454392)
Neoplasia. 2004 Sep-Oct;6(5):611-22. (PMID: 15548371)
Nat Chem Biol. 2009 Mar;5(3):157-65. (PMID: 19182783)
Leukemia. 2003 Jul;17(7):1263-93. (PMID: 12835716)
Nucleic Acids Res. 2004 Jul 1;32(Web Server issue):W217-21. (PMID: 15215384)
Annu Rev Pathol. 2015;10:473-510. (PMID: 25621663)
Cell. 2005 Jun 17;121(6):837-48. (PMID: 15960972)
Elife. 2016 Sep 08;5:. (PMID: 27608486)
Nature. 2000 Aug 17;406(6797):747-52. (PMID: 10963602)
Trends Biochem Sci. 1995 Aug;20(8):303-7. (PMID: 7667888)
CA Cancer J Clin. 2019 Jan;69(1):7-34. (PMID: 30620402)
Nature. 2016 Mar 3;531(7592):47-52. (PMID: 26909576)
Nature. 2011 Jul 06;475(7354):106-9. (PMID: 21734707)
Nat Rev Dis Primers. 2016 Apr 21;2:16022. (PMID: 27158978)
Cell Death Differ. 2018 Jan;25(1):133-143. (PMID: 29125602)
Nat Cell Biol. 2017 May;19(5):518-529. (PMID: 28414315)
Oncol Res. 2019 Sep 23;27(9):1015-1023. (PMID: 29716672)
Mol Cell Biol. 2005 Jul;25(13):5699-711. (PMID: 15964824)
Traffic. 2013 Feb;14(2):194-204. (PMID: 23057818)
Proc Natl Acad Sci U S A. 2015 Jun 23;112(25):7731-6. (PMID: 26056275)
Hepatogastroenterology. 2008 Nov-Dec;55(88):2016-27. (PMID: 19260470)
Cell. 2016 Dec 1;167(6):1540-1554.e12. (PMID: 27912061)
Cancer Cell. 2009 Sep 8;16(3):259-66. (PMID: 19732725)
Clin Cancer Res. 2018 Jul 15;24(14):3397-3408. (PMID: 29661777)
Mol Cancer Res. 2017 Oct;15(10):1331-1340. (PMID: 28684637)
Cell. 2017 Feb 9;168(4):629-643. (PMID: 28187285)
Am J Pathol. 1993 May;142(5):1534-43. (PMID: 8494051)
Cell Res. 2002 Mar;12(1):9-18. (PMID: 11942415)
Development. 2017 Mar 1;144(5):737-754. (PMID: 28246209)
Biomed Pharmacother. 2019 Aug;116:109023. (PMID: 31150989)
J Cell Biol. 1995 Dec;131(6 Pt 2):1715-26. (PMID: 8557739)
PLoS One. 2015 Sep 22;10(9):e0138896. (PMID: 26393359)
Cell. 2015 Jun 4;161(6):1345-60. (PMID: 26004068)
Science. 2005 Dec 2;310(5753):1452-6. (PMID: 16322447)
Genes Dev. 2005 Jun 1;19(11):1354-64. (PMID: 15937222)
Nat Rev Clin Oncol. 2015 Jun;12(6):319-34. (PMID: 25824606)
Nature. 2014 Apr 3;508(7494):118-22. (PMID: 24670642)
Cancer Lett. 2018 Dec 1;438:52-62. (PMID: 30213559)
Oncogene. 2005 Oct 6;24(44):6626-36. (PMID: 16103885)
Annu Rev Immunol. 2014;32:513-45. (PMID: 24555472)
J Cell Biol. 2009 Nov 16;187(4):449-53. (PMID: 19948493)
Nature. 2008 Jun 19;453(7198):1112-6. (PMID: 18500333)
Grant Information:: R01 CA200919 United States CA NCI NIH HHS; R03 CA221926 United States CA NCI NIH HHS; P30 CA013148 United States CA NCI NIH HHS; R01 CA218008 United States CA NCI NIH HHS; R03 CA230815 United States CA NCI NIH HHS; R21 CA229927 United States CA NCI NIH HHS; R01 CA196566 United States CA NCI NIH HHS
Contributed Indexing:: Keywords: Golgi complex; IFN-stimulated genes; KLF7; metastasis; pancreatic cancer
Substance Nomenclature:: 0 (DLG3 protein, human)
0 (KLF7 protein, human)
0 (Klf7 protein, mouse)
0 (Kruppel-Like Transcription Factors)
0 (Nuclear Proteins)
0 (Transcription Factors)
Entry Date(s):: Date Created: 20200521 Date Completed: 20200904 Latest Revision: 20231213
Update Code:: 20240105
PubMed Central ID:: PMC7275752
DOI:: 10.1073/pnas.2005156117
PMID:: 32430335
: Czasopismo naukowe

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a dismal prognosis. Currently, there is no effective therapy for PDAC, and a detailed molecular and functional evaluation of PDACs is needed to identify and develop better therapeutic strategies. Here we show that the transcription factor Krüppel-like factor 7 (KLF7) is overexpressed in PDACs, and that inhibition of KLF7 blocks PDAC tumor growth and metastasis in cell culture and in mice. KLF7 expression in PDACs can be up-regulated due to activation of a MAP kinase pathway or inactivation of the tumor suppressor p53, two alterations that occur in a large majority of PDACs. ShRNA-mediated knockdown of KLF7 inhibits the expression of IFN-stimulated genes (ISGs), which are necessary for KLF7-mediated PDAC tumor growth and metastasis. KLF7 knockdown also results in the down-regulation of Discs Large MAGUK Scaffold Protein 3 (DLG3), resulting in Golgi complex fragmentation, and reduced protein glycosylation, leading to reduced secretion of cancer-promoting growth factors, such as chemokines. Genetic or pharmacologic activation of Golgi complex fragmentation blocks PDAC growth and metastasis similar to KLF7 inhibition. Our results demonstrate a therapeutically amenable, KLF7-driven pathway that promotes PDAC growth and metastasis by activating ISGs and maintaining Golgi complex integrity.
Competing Interests: The authors declare no competing interest.

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