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The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer.

Li Z, Wang Y, Qiu J, Li Q, Yuan C, Zhang W, Wang D, Ye J, Jiang H, Yang J, Cheng J - Oncotarget (2013)

Bottom Line: We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers.Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin.Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil.

View Article: PubMed Central - PubMed

Affiliation: Head Neck Cancer Center, Institute of Stomatology, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China PRC.

ABSTRACT
EZH2, a core member of the Polycomb Repressor Complex 2 (PRC2), mediates transcriptional silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27), which plays key roles in cancer initiation and progression. Here, we investigated the expression pattern and biological roles of EZH2 in tongue tumorigenesis by loss-of-function assays using small interference RNA and EZH2 inhibitor DZNep. Also we determined the therapeutic efficiency of DZNep against tongue cancer in vivo. We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers. Elevated EZH2 correlated with shorter overall survival and showed significant and independent prognostic importance in patients with tongue cancer. Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin. Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil. Furthermore, intratumoral EZH2 inhibition induced by DZNep intraperitoneal administration significantly attenuated tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that EZH2 serves as a key driver with multiple oncogenic functions during tongue tumorigenesis and a new biomarker for tongue cancer diagnosis and prognostic prediction. These findings open up possibilities for therapeutic intervention against EZH2 in tongue cancer.

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DZNep inhibits endogenous EZH2 by proteosome-mediated protein degradationA: DZNep inhibits EZH2 in a dose-and time-dependent manner in both Cal27 and Tca8113 cells. Representative images of WB are shown. B: H3k27me3 was simultaneously reduced following DZNep exposure (5μM, 72h) in both Cal27 and Tca8113 cells. Representative images of WB are shown. C: Real-time RT-PCR assay for EZH2 mRNA levels following DZNep exposure (5μM, 24h) in both Cal27 and Tca8113 cells. D: EZH2 protein was determined by Western blotting after Cal27 was exposed to DZNep or/and the proteosome inhibitor MG132 for 24h. Representative image of WB were shown. Data showed here are mean ± SD from three independent experiments, Student's t-test.
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Figure 2: DZNep inhibits endogenous EZH2 by proteosome-mediated protein degradationA: DZNep inhibits EZH2 in a dose-and time-dependent manner in both Cal27 and Tca8113 cells. Representative images of WB are shown. B: H3k27me3 was simultaneously reduced following DZNep exposure (5μM, 72h) in both Cal27 and Tca8113 cells. Representative images of WB are shown. C: Real-time RT-PCR assay for EZH2 mRNA levels following DZNep exposure (5μM, 24h) in both Cal27 and Tca8113 cells. D: EZH2 protein was determined by Western blotting after Cal27 was exposed to DZNep or/and the proteosome inhibitor MG132 for 24h. Representative image of WB were shown. Data showed here are mean ± SD from three independent experiments, Student's t-test.

Mentions: Previous reports have indicate that DZNep potently depleted the core proteins of Polycomb complex including EZH2 and robustly triggered anti-cancer therapeutic effects in several cancer cells[19, 20]. To determine whether the inhibitory effects of DZNep on EZH2 expression exist in tongue cancer cells, we first measured the EZH2 abundance change following various concentrations and time courses of DZNep treatment. Cal27 and Tca8113 were incubated with various concentrations of DZNep(1, 2.5, 5μM) for varying time courses and then subjected to western blotting assay. As shown in Fig. 2A, DZNep induced a time-dependent and dose-dependent decrease of EZH2 in these two cell lines. The most significant inhibitions were observed when cells were treated with 5 μM DZNep and for 72h. As H3K27 tri-methylation is mainly catalyzed by EZH2 and associated with the PRC2-mediated epigenetic repression in cancer, we then monitored the changes of H3K27 expression after cells treated with DZNep. As expected, the abundance of H3K27me3 was pronouncedly downregulated following DZNep incubation (Fig.2B).


The polycomb group protein EZH2 is a novel therapeutic target in tongue cancer.

Li Z, Wang Y, Qiu J, Li Q, Yuan C, Zhang W, Wang D, Ye J, Jiang H, Yang J, Cheng J - Oncotarget (2013)

DZNep inhibits endogenous EZH2 by proteosome-mediated protein degradationA: DZNep inhibits EZH2 in a dose-and time-dependent manner in both Cal27 and Tca8113 cells. Representative images of WB are shown. B: H3k27me3 was simultaneously reduced following DZNep exposure (5μM, 72h) in both Cal27 and Tca8113 cells. Representative images of WB are shown. C: Real-time RT-PCR assay for EZH2 mRNA levels following DZNep exposure (5μM, 24h) in both Cal27 and Tca8113 cells. D: EZH2 protein was determined by Western blotting after Cal27 was exposed to DZNep or/and the proteosome inhibitor MG132 for 24h. Representative image of WB were shown. Data showed here are mean ± SD from three independent experiments, Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3926847&req=5

Figure 2: DZNep inhibits endogenous EZH2 by proteosome-mediated protein degradationA: DZNep inhibits EZH2 in a dose-and time-dependent manner in both Cal27 and Tca8113 cells. Representative images of WB are shown. B: H3k27me3 was simultaneously reduced following DZNep exposure (5μM, 72h) in both Cal27 and Tca8113 cells. Representative images of WB are shown. C: Real-time RT-PCR assay for EZH2 mRNA levels following DZNep exposure (5μM, 24h) in both Cal27 and Tca8113 cells. D: EZH2 protein was determined by Western blotting after Cal27 was exposed to DZNep or/and the proteosome inhibitor MG132 for 24h. Representative image of WB were shown. Data showed here are mean ± SD from three independent experiments, Student's t-test.
Mentions: Previous reports have indicate that DZNep potently depleted the core proteins of Polycomb complex including EZH2 and robustly triggered anti-cancer therapeutic effects in several cancer cells[19, 20]. To determine whether the inhibitory effects of DZNep on EZH2 expression exist in tongue cancer cells, we first measured the EZH2 abundance change following various concentrations and time courses of DZNep treatment. Cal27 and Tca8113 were incubated with various concentrations of DZNep(1, 2.5, 5μM) for varying time courses and then subjected to western blotting assay. As shown in Fig. 2A, DZNep induced a time-dependent and dose-dependent decrease of EZH2 in these two cell lines. The most significant inhibitions were observed when cells were treated with 5 μM DZNep and for 72h. As H3K27 tri-methylation is mainly catalyzed by EZH2 and associated with the PRC2-mediated epigenetic repression in cancer, we then monitored the changes of H3K27 expression after cells treated with DZNep. As expected, the abundance of H3K27me3 was pronouncedly downregulated following DZNep incubation (Fig.2B).

Bottom Line: We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers.Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin.Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil.

View Article: PubMed Central - PubMed

Affiliation: Head Neck Cancer Center, Institute of Stomatology, Affiliated Stomatological Hospital, Nanjing Medical University, Jiangsu, China PRC.

ABSTRACT
EZH2, a core member of the Polycomb Repressor Complex 2 (PRC2), mediates transcriptional silencing by catalyzing the trimethylation of histone 3 lysine 27 (H3K27), which plays key roles in cancer initiation and progression. Here, we investigated the expression pattern and biological roles of EZH2 in tongue tumorigenesis by loss-of-function assays using small interference RNA and EZH2 inhibitor DZNep. Also we determined the therapeutic efficiency of DZNep against tongue cancer in vivo. We found that aberrantly overexpressed EZH2 was associated with pathological grade, cervical nodes metastasis and Ki-67 expression in tongue cancers. Elevated EZH2 correlated with shorter overall survival and showed significant and independent prognostic importance in patients with tongue cancer. Both genetic and pharmacological depletion of EZH2 inhibited cell proliferation, migration, invasion and colony formation and decreased CD44+ subpopulation probably in part through modulating p16, p21 and E-caherin. Moreover, DZNep enhanced the anticancer effects of 5-Fluorouracil. Furthermore, intratumoral EZH2 inhibition induced by DZNep intraperitoneal administration significantly attenuated tumor growth in a tongue cancer xenograft model. Taken together, our results indicate that EZH2 serves as a key driver with multiple oncogenic functions during tongue tumorigenesis and a new biomarker for tongue cancer diagnosis and prognostic prediction. These findings open up possibilities for therapeutic intervention against EZH2 in tongue cancer.

Show MeSH
Related in: MedlinePlus