TCEAL7 inhibition of c-Myc activity in alternative lengthening of telomeres regulates hTERT expression.
Replicative senescence forms a major barrier to tumor progression. Cancer cells bypass this by using one of the two known telomere maintenance mechanisms: telomerase or the recombination-based alternative lengthening of telomeres (ALT) mechanism. The molecular details of ALT are currently poorly understood. We have previously shown that telomerase is actively repressed through complex networks of kinase, gene expression, and chromatin regulation. In this study, we aimed to gain further understanding of the role of kinases in the regulation of telomerase expression in ALT cells. Using a whole human kinome small interfering RNA (siRNA) screen, we highlighted 106 kinases whose expression is linked to human telomerase reverse transcriptase (hTERT) promoter activity. Network modeling of transcriptional regulation implicated c-Myc as a key regulator of the 106 kinase hits. Given our previous observations of lower c-Myc activity in ALT cells, we further explored its potential to regulate telomerase expression in ALT. We found increased c-Myc binding at the hTERT promoter in telomerase-positive compared with ALT cells, although no expression differences in c-Myc, Mad, or Max were observed between ALT and telomerase-positive cells that could explain decreased c-Myc activity in ALT. Instead, we found increased expression of the c-Myc competitive inhibitor TCEAL7 in ALT cells and tumors and that alteration of TCEAL7 expression levels in ALT and telomerase-positive cells affects hTERT expression. Lower c-Myc activity in ALT may therefore be obtained through TCEAL7 regulation. Thus, TCEAL7 may present an interesting novel target for cancer therapy, which warrants further investigation.
Lafferty-Whyte
Kyle
K
University of Glasgow, CRUK Beatson Laboratories, Glasgow, UK.
Bilsland
Alan
A
Hoare
Stacey F
SF
Burns
Sharon
S
Zaffaroni
Nadia
N
Cairney
Claire J
CJ
Keith
William Nicol
WN
D045744:Cell Line, Tumor; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019098:Telomerase / Q000096:biosynthesis* / Q000235:genetics; D016615:Telomere / Q000378:metabolism* / Q000473:pathology; D015533:Transcriptional Activation; D014162:Transfection
C489427:MYC protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C503109:TCEAL7 protein, human; D019098:Telomerase
Oncogene. 2008 Mar 20;27(13):1905-15
17906696
Nat Rev Cancer. 2008 Dec;8(12):976-90
19029958
PLoS One. 2009 Jul 31;4(7):e6459
19649288
Proc Natl Acad Sci U S A. 2007 Aug 7;104(32):13028-33
17664422
Genome Biol. 2003;4(10):R69
14519204
Gynecol Oncol. 2009 Aug;114(2):260-4
19419758
Cancer Cell. 2008 Aug 12;14(2):146-55
18691549
Neoplasia. 2005 Nov;7(11):1020-9
16331888
Cancer Cell. 2007 May;11(5):461-9
17433785
Biochem Soc Trans. 2009 Jun;37(Pt 3):589-95
19442255
Oncogene. 2005 Jul 28;24(32):5089-100
15870691
Oncogene. 2009 Oct 29;28(43):3765-74
19684619
Cancer Res. 2005 Sep 1;65(17):7585-90
16140922
FASEB J. 2010 Feb;24(2):579-86
19762557
Clin Cancer Res. 2008 Jul 1;14(13):4134-40
18593991
Cancer Res. 2006 Sep 1;66(17):8918-24
16951210
Oncogene. 2008 Nov 6;27(52):6623-34
18679422
Oncogene. 2008 Dec 11;27(58):7223-34
18806825
Clin Cancer Res. 2005 Jan 1;11(1):217-25
15671549
Cell. 1993 Jan 29;72(2):211-22
8425218
Cell Cycle. 2009 Oct 15;8(20):3373-8
19806010
Neoplasia. 2008 Oct;10(10):1066-72
18813356
Genes Chromosomes Cancer. 2004 Oct;41(2):155-62
15287028
Cancer Lett. 2009 Dec 28;286(2):172-9
19560862
Cancer Res. 2003 Apr 15;63(8):1759-63
12702558
Cell. 1993 Jan 29;72(2):233-45
8425220
Cancer Lett. 2003 Jul 18;197(1-2):125-30
12880971
Lancet. 2003 Mar 8;361(9360):836-8
12642053
Curr Opin Cell Biol. 2008 Apr;20(2):150-5
18353625
Br J Cancer. 2008 Apr 22;98(8):1467-74
18414473
Nat Rev Cancer. 2009 Jun;9(6):441-4
19461668