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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 regulates translation of HES1 and SIRT1 mRNAs(A and B) WB of CPEB1, SIRT1 and HES1 in CSC2 (A) and X01 (B) with serum or without serum. (C and D) WB of CPEB1, SIRT1 and HES1 in CSC2 infected with CPEB1-expressing lentiviral or control construct (C) and infected with shCPEB1-expressing lentiviral or control construct (D). Expression level of SIRT1 and HES1 proteins were quantified with ImageJ software. Each protein level was normalized with that of β-Actin (loading control). (E and F) qRT-PCR of SIRT1 and HES1 in CSC2 infected with CPEB1-expressing lentiviral or control construct (E) and infected with shCPEB1-expressing lentiviral or control construct (F).
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Figure 5: CPEB1 regulates translation of HES1 and SIRT1 mRNAs(A and B) WB of CPEB1, SIRT1 and HES1 in CSC2 (A) and X01 (B) with serum or without serum. (C and D) WB of CPEB1, SIRT1 and HES1 in CSC2 infected with CPEB1-expressing lentiviral or control construct (C) and infected with shCPEB1-expressing lentiviral or control construct (D). Expression level of SIRT1 and HES1 proteins were quantified with ImageJ software. Each protein level was normalized with that of β-Actin (loading control). (E and F) qRT-PCR of SIRT1 and HES1 in CSC2 infected with CPEB1-expressing lentiviral or control construct (E) and infected with shCPEB1-expressing lentiviral or control construct (F).

Mentions: When cells were cultured in the presence of serum, high CPEB1 expression was inversely correlated with the levels of SIRT1 and HES1 proteins in GSCs (Figures 5A and 5B). Furthermore, CPEB1 overexpression significantly decreased SIRT1 and HES1 expression (Figure 5C). In contrast, CPEB1 depletion in CSC2 resulted in dramatic increases in both SIRT1 and HES1 expression (Figure 5D), whereas CPEB1 overexpression or depletion did not alter the expression of SIRT1 and HES1 mRNAs (Figures 5E and 5F), suggesting that the regulation occurred at the posttranscriptional level. Taken together, these findings indicate that CPEB1 functions as a translational repressor of SIRT1 and HES1 expression in GSCs.


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 regulates translation of HES1 and SIRT1 mRNAs(A and B) WB of CPEB1, SIRT1 and HES1 in CSC2 (A) and X01 (B) with serum or without serum. (C and D) WB of CPEB1, SIRT1 and HES1 in CSC2 infected with CPEB1-expressing lentiviral or control construct (C) and infected with shCPEB1-expressing lentiviral or control construct (D). Expression level of SIRT1 and HES1 proteins were quantified with ImageJ software. Each protein level was normalized with that of β-Actin (loading control). (E and F) qRT-PCR of SIRT1 and HES1 in CSC2 infected with CPEB1-expressing lentiviral or control construct (E) and infected with shCPEB1-expressing lentiviral or control construct (F).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196161&req=5

Figure 5: CPEB1 regulates translation of HES1 and SIRT1 mRNAs(A and B) WB of CPEB1, SIRT1 and HES1 in CSC2 (A) and X01 (B) with serum or without serum. (C and D) WB of CPEB1, SIRT1 and HES1 in CSC2 infected with CPEB1-expressing lentiviral or control construct (C) and infected with shCPEB1-expressing lentiviral or control construct (D). Expression level of SIRT1 and HES1 proteins were quantified with ImageJ software. Each protein level was normalized with that of β-Actin (loading control). (E and F) qRT-PCR of SIRT1 and HES1 in CSC2 infected with CPEB1-expressing lentiviral or control construct (E) and infected with shCPEB1-expressing lentiviral or control construct (F).
Mentions: When cells were cultured in the presence of serum, high CPEB1 expression was inversely correlated with the levels of SIRT1 and HES1 proteins in GSCs (Figures 5A and 5B). Furthermore, CPEB1 overexpression significantly decreased SIRT1 and HES1 expression (Figure 5C). In contrast, CPEB1 depletion in CSC2 resulted in dramatic increases in both SIRT1 and HES1 expression (Figure 5D), whereas CPEB1 overexpression or depletion did not alter the expression of SIRT1 and HES1 mRNAs (Figures 5E and 5F), suggesting that the regulation occurred at the posttranscriptional level. Taken together, these findings indicate that CPEB1 functions as a translational repressor of SIRT1 and HES1 expression in GSCs.

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