Silencing PinX1 compromises telomere length maintenance as well as tumorigenicity in telomerase-positive human cancer cells.
The nucleolar protein PinX1 has been proposed to be a putative tumor suppressor due to its binding to and inhibition of the catalytic activity of telomerase, an enzyme that is highly expressed in most human cancers in which it counteracts telomere shortening-induced senescence to confer cancer cell immortalization. However, the role of PinX1 in telomere regulation, as well as in cancer, is still poorly understood. In this study, we showed that the PinX1 protein is constitutively expressed in various human cells regardless of their telomerase activity and malignant status. Most interestingly, we found that silencing PinX1 expression by a potent short hairpin RNA construct led to a robust telomere length shortening and growth inhibition in telomerase-positive but not in telomerase-negative human cancer cells. We further showed that silencing PinX1 significantly reduced the endogenous association of telomerase with the Pot1-containing telomeric protein complex, and therefore, could account for the phenotypic telomere shortening in the affected telomerase-positive cancer cells. Our results thus reveal a novel positive role for PinX1 in telomerase/telomere regulations and suggest that the constitutive expression of PinX1 attributes to telomere maintenance by telomerase and tumorigenicity in cancer cells.
Zhang
Bin
B
Laboratory of Tumor and Molecular Biology, Beijing Institute of Biotechnology, Department of Urology, General Hospital of People's Liberation Army, Beijing, P.R. China.
Bai
Yun Xiu
YX
Ma
Hang Hang
HH
Feng
Feng
F
Jin
Rui
R
Wang
Zhi Long
ZL
Lin
Jian
J
Sun
Shi Peng
SP
Yang
Pingxun
P
Wang
Xiao Xiong
XX
Huang
Pei Tang
PT
Huang
Cui Fen
CF
Peng
Ying
Y
Chen
Yang Chao
YC
Kung
Hsiang-Fu
HF
Huang
Jun Jian
JJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D034741:RNA, Small Interfering / Q000235:genetics; D000089804:Shelterin Complex; D019098:Telomerase / Q000096:biosynthesis / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics
D018797:Cell Cycle Proteins; C440808:PINX1 protein, human; C440849:POT1 protein, human; D034741:RNA, Small Interfering; D000089804:Shelterin Complex; D034501:Telomere-Binding Proteins; D025521:Tumor Suppressor Proteins; D005047:Etoposide; D019098:Telomerase