title: Silencing PinX1 compromises telomere length maintenance as well as tumorigenicity in telomerase-positive human cancer cells.
abstract: 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.
authors.affiliation: Laboratory of Tumor and Molecular Biology, Beijing Institute of Biotechnology, Department of Urology, General Hospital of People's Liberation Army, Beijing, P.R. China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Yun Xiu
authors.initials: YX
authors.lastname: Bai
authors.forename: Hang Hang
authors.initials: HH
authors.lastname: Ma
authors.forename: Feng
authors.initials: F
authors.lastname: Feng
authors.forename: Rui
authors.initials: R
authors.lastname: Jin
authors.forename: Zhi Long
authors.initials: ZL
authors.lastname: Wang
authors.forename: Jian
authors.initials: J
authors.lastname: Lin
authors.forename: Shi Peng
authors.initials: SP
authors.lastname: Sun
authors.forename: Pingxun
authors.initials: P
authors.lastname: Yang
authors.forename: Xiao Xiong
authors.initials: XX
authors.lastname: Wang
authors.forename: Pei Tang
authors.initials: PT
authors.lastname: Huang
authors.forename: Cui Fen
authors.initials: CF
authors.lastname: Huang
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.forename: Yang Chao
authors.initials: YC
authors.lastname: Chen
authors.forename: Hsiang-Fu
authors.initials: HF
authors.lastname: Kung
authors.forename: Jun Jian
authors.initials: JJ
authors.lastname: Huang
mesh_terms: 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
chemical_list: 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