Silencing of Kruppel-like factor 2 by the histone methyltransferase EZH2 in human cancer View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2011-09-05

AUTHORS

H Taniguchi, F V Jacinto, A Villanueva, A F Fernandez, H Yamamoto, F J Carmona, S Puertas, V E Marquez, Y Shinomura, K Imai, M Esteller

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. More... »

PAGES

1988-1994

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/onc.2011.387

DOI

http://dx.doi.org/10.1038/onc.2011.387

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1002108250

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21892211


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33 schema:description 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.
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48 breast tumors
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51 cells
52 culture
53 depletion
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55 diminished expression
56 direct transcriptional repression
57 dissemination
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59 enhancer
60 epigenetic silencing
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63 factor 2
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65 family
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69 histone H3
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71 homolog 2
72 human cancers
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74 induction
75 interference
76 last setting
77 levels
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79 low tumorigenicity
80 lower mortality rate
81 malignancy
82 members
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84 mice
85 molecules
86 mortality rate
87 nude mice
88 oncogenesis
89 oncogenic phenotype
90 overall survival
91 patients
92 phenotype
93 polycomb group protein enhancer
94 polymerase
95 primary samples
96 prominent member
97 prostate
98 protein
99 protein enhancer
100 rate
101 regulator
102 repression
103 results
104 role
105 samples
106 serine 2
107 setting
108 shorter overall survival
109 significant anti-tumoral effects
110 silencing
111 small molecules
112 study
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