Wilms' tumour 1 can suppress hTERT gene expression and telomerase activity in clear cell renal cell carcinoma via multiple pathways.
BACKGROUND
Wilms' tumour 1 (WT1) gene was discovered as a tumour suppressor gene. Later findings have suggested that WT1 also can be oncogenic. This complexity is partly explained by the fact that WT1 has a number of target genes.


METHODS
WT1 and its target gene human telomerase reverse transcriptase (hTERT) were analysed in clear cell renal cell carcinoma (ccRCC). In vitro experiments were performed to examine the functional link between WT1 and hTERT by overexpression of WT1 isoforms in the ccRCC cell line, TK-10.


RESULTS
WT1 demonstrated lower RNA expression in ccRCC compared with renal cortical tissue, whereas hTERT was increased, showing a negative correlation between WT1 and hTERT (P=0.005). These findings were experimentally confirmed in vitro. The WT1 generated effect on hTERT promoter activity seemed complex, as several negative regulators of hTERT transcription, such as SMAD3, JUN (AP-1) and ETS1, were activated by WT1 overexpression. Downregulation of potential positive hTERT regulators, such as cMyc, AP-2α, AP-2γ, IRF1, NFX1 and GM-CSF, were also observed. Chromatin immunoprecipitation analysis verified WT1 binding to the hTERT, cMyc and SMAD3 promoters.


CONCLUSIONS
The collected data strongly indicate multiple pathways for hTERT regulation by WT1 in ccRCC.
Sitaram
R T
RT
Department of Medical Biosciences and Pathology, Umeå University, Umeå, Sweden.
Degerman
S
S
Ljungberg
B
B
Andersson
E
E
Oji
Y
Y
Sugiyama
H
H
Roos
G
G
Li
A
A
D002292:Carcinoma, Renal Cell / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006801:Humans; D007680:Kidney Neoplasms / Q000201:enzymology / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D025721:WT1 Proteins; C509186:TERT protein, human; D019098:Telomerase