Reprogramming of replicative senescence in hepatocellular carcinoma-derived cells.
Tumor cells have the capacity to proliferate indefinitely that is qualified as replicative immortality. This ability contrasts with the intrinsic control of the number of cell divisions in human somatic tissues by a mechanism called replicative senescence. Replicative immortality is acquired by inactivation of p53 and p16INK4a genes and reactivation of hTERT gene expression. It is unknown whether the cancer cell replicative immortality is reversible. Here, we show the spontaneous induction of replicative senescence in p53-and p16INK4a-deficient hepatocellular carcinoma cells. This phenomenon is characterized with hTERT repression, telomere shortening, senescence arrest, and tumor suppression. SIP1 gene (ZFHX1B) is partly responsible for replicative senescence, because short hairpin RNA-mediated SIP1 inactivation released hTERT repression and rescued clonal hepatocellular carcinoma cells from senescence arrest.
Ozturk
Nuri
N
Department of Molecular Biology and Genetics, Bilkent University, Bilkent, Ankara 06800, Turkey. ozturk@fen.bilkent.edu.tr
Erdal
Esra
E
Mumcuoglu
Mine
M
Akcali
Kamil C
KC
Yalcin
Ozden
O
Senturk
Serif
S
Arslan-Ergul
Ayca
A
Gur
Bala
B
Yulug
Isik
I
Cetin-Atalay
Rengul
R
Yakicier
Cengiz
C
Yagci
Tamer
T
Tez
Mesut
M
Ozturk
Mehmet
M
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation; D052138:Genes, Neoplasm; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D051379:Mice; D012097:Repressor Proteins / Q000235:genetics*; D019098:Telomerase / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000235:genetics; D000074165:Zinc Finger E-box Binding Homeobox 2
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D019098:Telomerase