Abstract
Gastric cancer (GC) is one of the leading causes of cancer death in the world. The role of histone deacetylase 4 (HDAC4) in specific cell and tissue types has been identified. However, its biological roles in the development of gastric cancer remain largely unexplored. Quantitative real time PCR (qRT-PCR) and western blot were used to analyze the expression of HDAC4 in the clinical samples. siRNA and overexpression of HDAC4 and siRNA p21 were used to study functional effects in a proliferation, a colony formation, a adenosine 5′-triphosphate (ATP) assay and reactive oxygen species(ROS) generation, cell cycle, cell apoptosis rates, and autophagy assays. HDAC4 was up-regulated in gastric cancer tissues and several gastric cancer cell lines. The proliferation, colony formation ability and ATP level were enhanced in HDAC4 overexpression SGC-7901 cells, but inhibited in HDAC4 knockdown SGC-7901 cells. HDAC4 knockdown led to G0/G1 phase cell arrest and caused apoptosis and ROS increase. Moreover, HDAC4 was found to inhibit p21 expression in gastric cancer SGC-7901 cells. p21 knockdown dramatically attenuated cell proliferation inhibition, cell cycle arrest, cell apoptosis promotion and autophagy up-regulation in HDAC4-siRNA SGC-7901 cells. We demonstrated that HDAC4 promotes gastric cancer cell progression mediated through the repression of p21. Our results provide an experimental basis for understanding the pro-tumor mechanism of HDAC4 as treatment for gastric cancer.
Highlights
Gastric cancer (GC) is the fourth most common malignancy and the second leading cause of cancer death worldwide [1]
Most targeted therapies focus on vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) related indications in advanced GC
Histone deacetylase 4 (HDAC4) expression were up-regulated in gastric cancer tissues and cell lines
Summary
Gastric cancer (GC) is the fourth most common malignancy and the second leading cause of cancer death worldwide [1]. Most targeted therapies focus on vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) related indications in advanced GC. Compounds against novel targets, such as mTOR [3], c-Met (hepatocyte growth factor receptor) [4], and HDACs, are under investigation. Histone deacetylase 4 (HDAC4), which is a class IIa HDAC, is known to exist in distinct transcriptional corepressor complexes. HDAC4 represses the expression of the cyclin-dependent kinase inhibitor p21 ( known as p21WAF1/Cip1) in human cancer cells through an Sp1dependent, p53-independent mechanism [6]. HDAC4 promotes the growth of colon cancer cells via repression of p21 [7]. Inactivation of HDAC4 by small interfering RNA or HDAC inhibitors suppresses neuronal cell death [8]
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