title: Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer.
abstract: The Kruppel-like factor (KLF) proteins are multitasked transcriptional regulators with an expanding tumor suppressor function. KLF2 is one of the prominent members of the family because of its diminished expression in malignancies and its growth-inhibitory, pro-apoptotic and anti-angiogenic roles. In this study, we show that epigenetic silencing of KLF2 occurs in cancer cells through direct transcriptional repression mediated by the Polycomb group protein Enhancer of Zeste Homolog 2 (EZH2). Binding of EZH2 to the 5'-end of KLF2 is also associated with a gain of trimethylated lysine 27 histone H3 and a depletion of phosphorylated serine 2 of RNA polymerase. Upon depletion of EZH2 by RNA interference, short hairpin RNA or use of the small molecule 3-Deazaneplanocin A, the expression of KLF2 was restored. The transfection of KLF2 in cells with EZH2-associated silencing showed a significant anti-tumoral effect, both in culture and in xenografted nude mice. In this last setting, KLF2 transfection was also associated with decreased dissemination and lower mortality rate. In EZH2-depleted cells, which characteristically have lower tumorigenicity, the induction of KLF2 depletion 'rescued' partially the oncogenic phenotype, suggesting that KLF2 repression has an important role in EZH2 oncogenesis. Most importantly, the translation of the described results to human primary samples demonstrated that patients with prostate or breast tumors with low levels of KLF2 and high expression of EZH2 had a shorter overall survival.
authors: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.
authors: H
authors: H
authors: Taniguchi
authors: F V
authors: FV
authors: Jacinto
authors: A
authors: A
authors: Villanueva
authors: A F
authors: AF
authors: Fernandez
authors: H
authors: H
authors: Yamamoto
authors: F J
authors: FJ
authors: Carmona
authors: S
authors: S
authors: Puertas
authors: V E
authors: VE
authors: Marquez
authors: Y
authors: Y
authors: Shinomura
authors: K
authors: K
authors: Imai
authors: M
authors: M
authors: Esteller
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2; D011471:Prostatic Neoplasms / Q000378:metabolism; D034622:RNA Interference; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D014157:Transcription Factors; C048460:3-deazaneplanocin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D000241:Adenosine