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CPEB1 modulates differentiation of glioma stem cells via downregulation of HES1 and SIRT1 expression.

Yin J, Park G, Lee JE, Park JY, Kim TH, Kim YJ, Lee SH, Yoo H, Kim JH, Park JB - Oncotarget (2014)

Bottom Line: This study identified CPEB1 as the key modulator that induces the differentiation of GSCs at the post-transcriptional level.Gain and loss of function experiments showed that CPEB1 expression reduced sphere formation ability and the expression of stemness markers such as Nestin and Notch.CPEB1 specifically suppressed the translation of HES1 and SIRT1 by interacting with a cytoplasmic polyadenylation element.

View Article: PubMed Central - PubMed

Affiliation: Specific Organs Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi , Korea. These authors contributed equally to this work.

ABSTRACT
Glioma stemness has been recognized as the most important reason for glioma relapse and drug resistance. Differentiation of glioma stem cells (GSCs) has been implicated as a novel approach to target recurrent glioma. However, the detailed molecular mechanism involved in the differentiation of GSCs has not yet been elucidated. This study identified CPEB1 as the key modulator that induces the differentiation of GSCs at the post-transcriptional level. Gain and loss of function experiments showed that CPEB1 expression reduced sphere formation ability and the expression of stemness markers such as Nestin and Notch. To elucidate the detailed molecular mechanism underlying the action of CPEB1, we investigated the interacting ribonome of the CPEB1 complex using a Ribonomics approach. CPEB1 specifically suppressed the translation of HES1 and SIRT1 by interacting with a cytoplasmic polyadenylation element. The expression profile of CPEB1 negatively correlated with overall survival in glioma patients. Overexpression of CPEB1 decreased the number of GSCs in an orthotopically implanted glioma animal model. These results suggest that CPEB1-mediated translational control is essential for the differentiation of GSCs and provides novel therapeutic concepts for differentiation therapy.

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CPEB1 expression is inversely correlated with glioma stemness and overall survival of glioma patients(A) The expression level of mRNA obtained from NT (non-tumor, n = 28), AST (astrocytoma, n = 148), OLG (oligodendrocytoma, n = 67) and GBM (glioblastoma multiforme, n = 228). Data obtained from the REMBRANDT database of the National Cancer Institute. (B) Overall survival between CPEB1 down-regulated (red curve) and intermediate (green curve) patients was analyzed. Data obtained from the REMBRANDT database of the National Cancer Institute (CPEB1 down-regulated >=2-fold, n = 133; CPEB1 intermediate, n = 210; p = 0.0111). (C) Real-time quantitative RT-PCR (qRT-PCR) results of CPEB1, differentiation markers (GFAP, S100β, and Tuj1), stemness markers (CD133 and SOX2) were obtained from serum treated or non-treated CSC2 glioma stem cells (GSCs). Graphs are representative of three independent experiments. All error bars represent mean ± s.e.m. (n = 3). *p<0.05; **p<0.01. (D) Western blots (WB) of CPEB1, GFAP, Sox2 and Nestin in serum treated or non-treated CSC2 (left) and X01 (right) GSCs.
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Figure 1: CPEB1 expression is inversely correlated with glioma stemness and overall survival of glioma patients(A) The expression level of mRNA obtained from NT (non-tumor, n = 28), AST (astrocytoma, n = 148), OLG (oligodendrocytoma, n = 67) and GBM (glioblastoma multiforme, n = 228). Data obtained from the REMBRANDT database of the National Cancer Institute. (B) Overall survival between CPEB1 down-regulated (red curve) and intermediate (green curve) patients was analyzed. Data obtained from the REMBRANDT database of the National Cancer Institute (CPEB1 down-regulated >=2-fold, n = 133; CPEB1 intermediate, n = 210; p = 0.0111). (C) Real-time quantitative RT-PCR (qRT-PCR) results of CPEB1, differentiation markers (GFAP, S100β, and Tuj1), stemness markers (CD133 and SOX2) were obtained from serum treated or non-treated CSC2 glioma stem cells (GSCs). Graphs are representative of three independent experiments. All error bars represent mean ± s.e.m. (n = 3). *p<0.05; **p<0.01. (D) Western blots (WB) of CPEB1, GFAP, Sox2 and Nestin in serum treated or non-treated CSC2 (left) and X01 (right) GSCs.

Mentions: To examine the possible role of CPEB1 in glioma malignancy, we analyzed the expression profile from the REMBRANDT (REpository for Molecular BRAin Neoplasia DaTa) database. CPEB1 expression was significantly lower in tumor samples from 148 patients with astrocytoma, 67 with oligodendroglioma, and 228 with GBM, than in 28 non-tumor brain tissue samples (Figure 1A). Overall survival was significantly longer in glioma patients with intermediate than low levels of CPEB1 expression (p = 0.0111; Figure 2B).


CPEB1 modulates differentiation of glioma stem cells via downregulation of HES1 and SIRT1 expression.

Yin J, Park G, Lee JE, Park JY, Kim TH, Kim YJ, Lee SH, Yoo H, Kim JH, Park JB - Oncotarget (2014)

CPEB1 expression is inversely correlated with glioma stemness and overall survival of glioma patients(A) The expression level of mRNA obtained from NT (non-tumor, n = 28), AST (astrocytoma, n = 148), OLG (oligodendrocytoma, n = 67) and GBM (glioblastoma multiforme, n = 228). Data obtained from the REMBRANDT database of the National Cancer Institute. (B) Overall survival between CPEB1 down-regulated (red curve) and intermediate (green curve) patients was analyzed. Data obtained from the REMBRANDT database of the National Cancer Institute (CPEB1 down-regulated >=2-fold, n = 133; CPEB1 intermediate, n = 210; p = 0.0111). (C) Real-time quantitative RT-PCR (qRT-PCR) results of CPEB1, differentiation markers (GFAP, S100β, and Tuj1), stemness markers (CD133 and SOX2) were obtained from serum treated or non-treated CSC2 glioma stem cells (GSCs). Graphs are representative of three independent experiments. All error bars represent mean ± s.e.m. (n = 3). *p<0.05; **p<0.01. (D) Western blots (WB) of CPEB1, GFAP, Sox2 and Nestin in serum treated or non-treated CSC2 (left) and X01 (right) GSCs.
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Related In: Results  -  Collection

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Figure 1: CPEB1 expression is inversely correlated with glioma stemness and overall survival of glioma patients(A) The expression level of mRNA obtained from NT (non-tumor, n = 28), AST (astrocytoma, n = 148), OLG (oligodendrocytoma, n = 67) and GBM (glioblastoma multiforme, n = 228). Data obtained from the REMBRANDT database of the National Cancer Institute. (B) Overall survival between CPEB1 down-regulated (red curve) and intermediate (green curve) patients was analyzed. Data obtained from the REMBRANDT database of the National Cancer Institute (CPEB1 down-regulated >=2-fold, n = 133; CPEB1 intermediate, n = 210; p = 0.0111). (C) Real-time quantitative RT-PCR (qRT-PCR) results of CPEB1, differentiation markers (GFAP, S100β, and Tuj1), stemness markers (CD133 and SOX2) were obtained from serum treated or non-treated CSC2 glioma stem cells (GSCs). Graphs are representative of three independent experiments. All error bars represent mean ± s.e.m. (n = 3). *p<0.05; **p<0.01. (D) Western blots (WB) of CPEB1, GFAP, Sox2 and Nestin in serum treated or non-treated CSC2 (left) and X01 (right) GSCs.
Mentions: To examine the possible role of CPEB1 in glioma malignancy, we analyzed the expression profile from the REMBRANDT (REpository for Molecular BRAin Neoplasia DaTa) database. CPEB1 expression was significantly lower in tumor samples from 148 patients with astrocytoma, 67 with oligodendroglioma, and 228 with GBM, than in 28 non-tumor brain tissue samples (Figure 1A). Overall survival was significantly longer in glioma patients with intermediate than low levels of CPEB1 expression (p = 0.0111; Figure 2B).

Bottom Line: This study identified CPEB1 as the key modulator that induces the differentiation of GSCs at the post-transcriptional level.Gain and loss of function experiments showed that CPEB1 expression reduced sphere formation ability and the expression of stemness markers such as Nestin and Notch.CPEB1 specifically suppressed the translation of HES1 and SIRT1 by interacting with a cytoplasmic polyadenylation element.

View Article: PubMed Central - PubMed

Affiliation: Specific Organs Cancer Branch, Research Institute, National Cancer Center, Goyang, Gyeonggi , Korea. These authors contributed equally to this work.

ABSTRACT
Glioma stemness has been recognized as the most important reason for glioma relapse and drug resistance. Differentiation of glioma stem cells (GSCs) has been implicated as a novel approach to target recurrent glioma. However, the detailed molecular mechanism involved in the differentiation of GSCs has not yet been elucidated. This study identified CPEB1 as the key modulator that induces the differentiation of GSCs at the post-transcriptional level. Gain and loss of function experiments showed that CPEB1 expression reduced sphere formation ability and the expression of stemness markers such as Nestin and Notch. To elucidate the detailed molecular mechanism underlying the action of CPEB1, we investigated the interacting ribonome of the CPEB1 complex using a Ribonomics approach. CPEB1 specifically suppressed the translation of HES1 and SIRT1 by interacting with a cytoplasmic polyadenylation element. The expression profile of CPEB1 negatively correlated with overall survival in glioma patients. Overexpression of CPEB1 decreased the number of GSCs in an orthotopically implanted glioma animal model. These results suggest that CPEB1-mediated translational control is essential for the differentiation of GSCs and provides novel therapeutic concepts for differentiation therapy.

Show MeSH
Related in: MedlinePlus