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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

Diagram for mechanism by which HDAC9 promotes cell proliferation and tumor progression in glioblastomaHDAC9 interacts with TAZ, enhances the expression of TAZ, and then phosphorylates EGFR. The phosphorylation of EGFR activates PI3K and ERK signaling pathways, increases the expression of cyclin E and CDK2, accelerates cell cycle progression, and then promotes cell proliferation and tumor progression in GBM.
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Figure 8: Diagram for mechanism by which HDAC9 promotes cell proliferation and tumor progression in glioblastomaHDAC9 interacts with TAZ, enhances the expression of TAZ, and then phosphorylates EGFR. The phosphorylation of EGFR activates PI3K and ERK signaling pathways, increases the expression of cyclin E and CDK2, accelerates cell cycle progression, and then promotes cell proliferation and tumor progression in GBM.

Mentions: As HDAC9 interacted with TAZ and knockdown of HDAC9 reduced the expression of TAZ, we hypothesized that TAZ might be a downstream effector of HDAC9 in GBM cells. To prove the inference, we forcedly expressed TAZ in HDAC9-knockdown cells, which induced TAZ down regulation. Western blot assay suggested that the expression of TAZ was rescued in the HDAC9-knockdown cells (Figure 7A, 7B, 7D and 7E). MTT assay was employed to analyze the abilities of cell proliferation and growth; results revealed that the proliferation ability was rescued after TAZ overexpressed in HDAC9-knockdown cells (Figure 7C and 7F). Cell cycle was analyzed by flow cytometry to examine whether TAZ promoted HDAC9-knockdown cells proliferation by rescuing the cell cycle progression. Overexpressed TAZ in HDAC9-knockdown cells significantly abrogated the effects of HDAC9 knockdown on the cell cycle progression. Similarly, the expression of cyclin E and CDK2 were also upregulated in the TAZ-rescued HDAC9-knockdown cells (Figure 7G–7I). The results were confirmed by soft agar assay in U87 cells, where the ability of colony formation was rescued after TAZ overexpressed in the HDAC9-knockdown cells (Figure 7J). The xenograft experiment revealed that the ability of tumor formation of TAZ-overexpressed HDAC9-knockdown U87 cells in vivo was also rescued (Figure 7K). Then we measured the activation of EGFR and its downstream signaling, the phosphorylation levels of EGFR, AKT and ERK1/2 were increased in the TAZ-rescued HDAC9-knockdown cells and xenograft tumors. The tumor suppressor p21 expression was decreased in the TAZ-overexpressed shHDAC9 cells and xenograft tumors (Figure 7L). Taken together, all the results demonstrated that TAZ was a crucial downstream effector of HDAC9 and HDAC9 promoted cell proliferation and tumor formation via TAZ-mediated EGFR activation in GBM Figure 8.


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)

Diagram for mechanism by which HDAC9 promotes cell proliferation and tumor progression in glioblastomaHDAC9 interacts with TAZ, enhances the expression of TAZ, and then phosphorylates EGFR. The phosphorylation of EGFR activates PI3K and ERK signaling pathways, increases the expression of cyclin E and CDK2, accelerates cell cycle progression, and then promotes cell proliferation and tumor progression in GBM.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Diagram for mechanism by which HDAC9 promotes cell proliferation and tumor progression in glioblastomaHDAC9 interacts with TAZ, enhances the expression of TAZ, and then phosphorylates EGFR. The phosphorylation of EGFR activates PI3K and ERK signaling pathways, increases the expression of cyclin E and CDK2, accelerates cell cycle progression, and then promotes cell proliferation and tumor progression in GBM.
Mentions: As HDAC9 interacted with TAZ and knockdown of HDAC9 reduced the expression of TAZ, we hypothesized that TAZ might be a downstream effector of HDAC9 in GBM cells. To prove the inference, we forcedly expressed TAZ in HDAC9-knockdown cells, which induced TAZ down regulation. Western blot assay suggested that the expression of TAZ was rescued in the HDAC9-knockdown cells (Figure 7A, 7B, 7D and 7E). MTT assay was employed to analyze the abilities of cell proliferation and growth; results revealed that the proliferation ability was rescued after TAZ overexpressed in HDAC9-knockdown cells (Figure 7C and 7F). Cell cycle was analyzed by flow cytometry to examine whether TAZ promoted HDAC9-knockdown cells proliferation by rescuing the cell cycle progression. Overexpressed TAZ in HDAC9-knockdown cells significantly abrogated the effects of HDAC9 knockdown on the cell cycle progression. Similarly, the expression of cyclin E and CDK2 were also upregulated in the TAZ-rescued HDAC9-knockdown cells (Figure 7G–7I). The results were confirmed by soft agar assay in U87 cells, where the ability of colony formation was rescued after TAZ overexpressed in the HDAC9-knockdown cells (Figure 7J). The xenograft experiment revealed that the ability of tumor formation of TAZ-overexpressed HDAC9-knockdown U87 cells in vivo was also rescued (Figure 7K). Then we measured the activation of EGFR and its downstream signaling, the phosphorylation levels of EGFR, AKT and ERK1/2 were increased in the TAZ-rescued HDAC9-knockdown cells and xenograft tumors. The tumor suppressor p21 expression was decreased in the TAZ-overexpressed shHDAC9 cells and xenograft tumors (Figure 7L). Taken together, all the results demonstrated that TAZ was a crucial downstream effector of HDAC9 and HDAC9 promoted cell proliferation and tumor formation via TAZ-mediated EGFR activation in GBM Figure 8.

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