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HDAC9 promotes glioblastoma growth via TAZ-mediated EGFR pathway activation.

Yang R, Wu Y, Wang M, Sun Z, Zou J, Zhang Y, Cui H - Oncotarget (2015)

Bottom Line: Also, HDAC9 interacted with TAZ, a key downstream effector of Hippo pathway.Knockdown of HDAC9 decreased the expression of TAZ.We found that overexpressed TAZ in HDAC9-knockdown cells abrogated the effects induced by HDAC9 silencing both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, P.R. China.

ABSTRACT
Histone deacetylase 9 (HDAC9), a member of class II HDACs, regulates a wide variety of normal and abnormal physiological functions. We found that HDAC9 is over-expressed in prognostically poor glioblastoma patients. Knockdown HDAC9 decreased proliferation in vitro and tumor formation in vivo. HDAC9 accelerated cell cycle in part by potentiating the EGFR signaling pathway. Also, HDAC9 interacted with TAZ, a key downstream effector of Hippo pathway. Knockdown of HDAC9 decreased the expression of TAZ. We found that overexpressed TAZ in HDAC9-knockdown cells abrogated the effects induced by HDAC9 silencing both in vitro and in vivo. We demonstrated that HDAC9 promotes tumor formation of glioblastoma via TAZ-mediated EGFR pathway activation, and provide the evidence for promising target for the treatment of glioblastoma.

No MeSH data available.


Related in: MedlinePlus

High HDAC9 expression is a prognostic indicator of poor survival in glioblastoma patients(A) Kaplan–Meier analysis of progression-free survival for the Frence database with the log rank test P value indicated. (B) Kaplan–Meier analysis of progression-free survival for the TCGA database with the log rank test P value was indicated. (C) Box plot of HDAC9 expression levels from non-tumor and recurrent GBM patients was shown. (D) Box plot of HDAC9 expression levels in the stage 2 and 5 tumors. (E) mRNA level of HDAC9 in glioblastoma cell lines, primary GBM cells and neuroblastoma cell lines by quantitative real time-PCR was analyzed. Values are shown as the mean ± SD (F) Western blot assay of HDAC9 expression in GBM cell lines, primary GBM cells and neuroblastoma cell lines was performed; representative blots are shown. Values are shown as the mean ± SD, *p < 0.05, **p < 0.01.
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Figure 1: High HDAC9 expression is a prognostic indicator of poor survival in glioblastoma patients(A) Kaplan–Meier analysis of progression-free survival for the Frence database with the log rank test P value indicated. (B) Kaplan–Meier analysis of progression-free survival for the TCGA database with the log rank test P value was indicated. (C) Box plot of HDAC9 expression levels from non-tumor and recurrent GBM patients was shown. (D) Box plot of HDAC9 expression levels in the stage 2 and 5 tumors. (E) mRNA level of HDAC9 in glioblastoma cell lines, primary GBM cells and neuroblastoma cell lines by quantitative real time-PCR was analyzed. Values are shown as the mean ± SD (F) Western blot assay of HDAC9 expression in GBM cell lines, primary GBM cells and neuroblastoma cell lines was performed; representative blots are shown. Values are shown as the mean ± SD, *p < 0.05, **p < 0.01.

Mentions: To determine whether alterations at the genetic locus of HDAC9 could be implicated in GBM patient prognosis, survival data from R2 genomics analysis and visualization platform database were used to evaluate the effects of HDAC9 on overall patient survival. HDAC9 was highly expressed in 472 out of 504 cases of glioma, and high expression very significantly correlated with reduced patient survival in French's data, p = 0.031 (Figure 1A). Similarly, in TCGA data set consisting of 88 patients, there were 33 cases with upregulation HDAC9, also confirmed that high level of HDAC9 was associated with poor prognosis, p = 0.041 (Figure 1B). Furthermore, contrasting to normal tissue and low grade astrocytoma, HDAC9 was significantly upregulated in GBM patients according to French's data, p < 0.05 (Figure 1C and 1D). Lastly, we measured the HDAC9 expression of GBM cells by quantitative real time-PCR and western blot assay, and we found that HDAC9 was commonly expressed in GBM cell lines (A172, U-87 MG, LN229) and primary GBM cells from T0807 and T1018 specimen, but it was low expressed in neuroblastoma cell lines (Figure 1E, 1F). All these results indicated that HDAC9 might function as an oncogene involved in the development and progression of GBM.


HDAC9 promotes glioblastoma growth via TAZ-mediated EGFR pathway activation.

Yang R, Wu Y, Wang M, Sun Z, Zou J, Zhang Y, Cui H - Oncotarget (2015)

High HDAC9 expression is a prognostic indicator of poor survival in glioblastoma patients(A) Kaplan–Meier analysis of progression-free survival for the Frence database with the log rank test P value indicated. (B) Kaplan–Meier analysis of progression-free survival for the TCGA database with the log rank test P value was indicated. (C) Box plot of HDAC9 expression levels from non-tumor and recurrent GBM patients was shown. (D) Box plot of HDAC9 expression levels in the stage 2 and 5 tumors. (E) mRNA level of HDAC9 in glioblastoma cell lines, primary GBM cells and neuroblastoma cell lines by quantitative real time-PCR was analyzed. Values are shown as the mean ± SD (F) Western blot assay of HDAC9 expression in GBM cell lines, primary GBM cells and neuroblastoma cell lines was performed; representative blots are shown. Values are shown as the mean ± SD, *p < 0.05, **p < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480706&req=5

Figure 1: High HDAC9 expression is a prognostic indicator of poor survival in glioblastoma patients(A) Kaplan–Meier analysis of progression-free survival for the Frence database with the log rank test P value indicated. (B) Kaplan–Meier analysis of progression-free survival for the TCGA database with the log rank test P value was indicated. (C) Box plot of HDAC9 expression levels from non-tumor and recurrent GBM patients was shown. (D) Box plot of HDAC9 expression levels in the stage 2 and 5 tumors. (E) mRNA level of HDAC9 in glioblastoma cell lines, primary GBM cells and neuroblastoma cell lines by quantitative real time-PCR was analyzed. Values are shown as the mean ± SD (F) Western blot assay of HDAC9 expression in GBM cell lines, primary GBM cells and neuroblastoma cell lines was performed; representative blots are shown. Values are shown as the mean ± SD, *p < 0.05, **p < 0.01.
Mentions: To determine whether alterations at the genetic locus of HDAC9 could be implicated in GBM patient prognosis, survival data from R2 genomics analysis and visualization platform database were used to evaluate the effects of HDAC9 on overall patient survival. HDAC9 was highly expressed in 472 out of 504 cases of glioma, and high expression very significantly correlated with reduced patient survival in French's data, p = 0.031 (Figure 1A). Similarly, in TCGA data set consisting of 88 patients, there were 33 cases with upregulation HDAC9, also confirmed that high level of HDAC9 was associated with poor prognosis, p = 0.041 (Figure 1B). Furthermore, contrasting to normal tissue and low grade astrocytoma, HDAC9 was significantly upregulated in GBM patients according to French's data, p < 0.05 (Figure 1C and 1D). Lastly, we measured the HDAC9 expression of GBM cells by quantitative real time-PCR and western blot assay, and we found that HDAC9 was commonly expressed in GBM cell lines (A172, U-87 MG, LN229) and primary GBM cells from T0807 and T1018 specimen, but it was low expressed in neuroblastoma cell lines (Figure 1E, 1F). All these results indicated that HDAC9 might function as an oncogene involved in the development and progression of GBM.

Bottom Line: Also, HDAC9 interacted with TAZ, a key downstream effector of Hippo pathway.Knockdown of HDAC9 decreased the expression of TAZ.We found that overexpressed TAZ in HDAC9-knockdown cells abrogated the effects induced by HDAC9 silencing both in vitro and in vivo.

View Article: PubMed Central - PubMed

Affiliation: State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400715, P.R. China.

ABSTRACT
Histone deacetylase 9 (HDAC9), a member of class II HDACs, regulates a wide variety of normal and abnormal physiological functions. We found that HDAC9 is over-expressed in prognostically poor glioblastoma patients. Knockdown HDAC9 decreased proliferation in vitro and tumor formation in vivo. HDAC9 accelerated cell cycle in part by potentiating the EGFR signaling pathway. Also, HDAC9 interacted with TAZ, a key downstream effector of Hippo pathway. Knockdown of HDAC9 decreased the expression of TAZ. We found that overexpressed TAZ in HDAC9-knockdown cells abrogated the effects induced by HDAC9 silencing both in vitro and in vivo. We demonstrated that HDAC9 promotes tumor formation of glioblastoma via TAZ-mediated EGFR pathway activation, and provide the evidence for promising target for the treatment of glioblastoma.

No MeSH data available.


Related in: MedlinePlus