HDAC9 promotes glioblastoma growth via TAZ-mediated EGFR pathway activation

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.

HMGCR positively regulated the growth and migration of glioblastoma cells

“…Moreover, CTGF, one of the target genes of YAP/TAZ signaling, was reported to be over-expressed in glioblastoma and regulated the malignant behaviors of cancer cells (Ernst et al, 2010;Romao et al, 2013). Several important regulators for YAP/TAZ signaling, such as HDAC9, Praja2 and so on, was found in the glioblastoma (Lignitto et al, 2013;Yang et al, 2015). However, whether metabolic clues could regulate the YAP/TAZ signaling was poorly understood.…”

“…CD44 was upregulated in glioblastoma and its depletion blocked the growth and tumorigenesis of glioblastoma by inhibiting TAZ/YAP signaling . Also, TAZ was reported to interact with histone deacetylase 9 (HDAC9) and knocking down of TAZ attenuated the oncogenic effects of HDAC9 in glioblastoma cells (Yang et al, 2015). However, how metabolic clues regulated the YAP/TAZ signaling remains largely unknown.…”

Tigecycline Inhibits Glioma Growth by Regulating miRNA-199b-5p–HES1–AKT Pathway

“…Five-to 6-week-old male nude mice were used in the experiments. Subcuticular injections were performed following a previous protocol with minor modifications (28). Briefly, U87 (1 Â 10 6 cells in 100 mL of PBS) were inoculated subcutaneously into the right flank of nude mice.…”

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“…In addition to their role in junction formation and stabilization, polarity proteins also impact cellular proliferation and their loss can block apoptosis, when in conjunction with oncogenes, can significantly increase tumor growth and invasion [48]. Of note, increased TAZ has been shown to activate the EGFR pathway, which can then result in a loss of E-cadherin expression at adherence junctions, drive migration, increase CD44 expression, and promote growth in soft agar and mammospheres [30,31,36]. It is interesting to note that loss of Llgl1 results in a downregulation of E-cadherin, as well as cell migratory behavior indicative of a loss of cell-cell junctions.…”

“…Characteristics that define these cells include serial transplantation in vitro and in vivo, and the expression of a variety of surface markers, including CD44 hi /CD24 lo , CD44 hi , and CD49f lo , among others [25][26][27][28][29]. Of note, TAZ nuclear translocation is known to potentiate EGFR signaling pathways, which in turn can increase CD44 transcription and stem cell characteristics [30,31]. Due to the connection between receptor localization within a cell and its ability to activate these pathways, an epithelial population may possess a plasticity depending upon their state of polarity.…”