title: TCEAL7 inhibition of c-Myc activity in alternative lengthening of telomeres regulates hTERT expression.
abstract: 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.
authors.affiliation: University of Glasgow, CRUK Beatson Laboratories, Glasgow, UK.
authors.forename: Kyle
authors.initials: K
authors.lastname: Lafferty-Whyte
authors.forename: Alan
authors.initials: A
authors.lastname: Bilsland
authors.forename: Stacey F
authors.initials: SF
authors.lastname: Hoare
authors.forename: Sharon
authors.initials: S
authors.lastname: Burns
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Cairney
authors.forename: William Nicol
authors.initials: WN
authors.lastname: Keith
mesh_terms: 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
chemical_list: C489427:MYC protein, human; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C503109:TCEAL7 protein, human; D019098:Telomerase
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