Abstract
N25, a novel histone deacetylase inhibitor, was created through structural modification of suberoylanilide hydroxamic acid. To evaluate the anti-tumor activity of N25 and clarify its molecular mechanism of inducing autophagy in glioma cells, we investigated its in vitro anti-proliferative effect and in vivo anticancer effect. Moreover, we detected whether N25 induces autophagy in glioma cells by transmission electron microscope and analyzed the protein expression level of HDAC3, Tip60, LC3 in glioma samples by western blot. We additionally analyzed the protein expression level of HDAC3, Tip60, ULK1 (Atg1), and Beclin-1 (Atg6) after treatment with N25 in glioma cells. Our results showed that the anti-tumor activity of N25 in glioma cells is slightly stronger than SAHA both in vitro and in vivo. We found that N25 induced autophagy, and HDAC3 was significantly elevated and Tip60 and LC3 significantly decreased in glioma samples compared with normal brain tissues. Nevertheless, N25 inhibited HDAC3 and up-regulated the protein expression of Tip60, ULK1 (Atg1), and Beclin-1 (Atg6) after treatment of glioma cells with N25. In conclusion, these data suggest that N25 has striking anti-tumor activity in part due to inhibition of HDAC3. Additionally, N25 may induce autophagy through inhibiting HDAC3.
Highlights
Glioma is both the most common and lethal primary brain tumor which occurs in adults and children [1, 2]
We detected whether N25 induces autophagy in glioma cells by transmission electron microscope and analyzed the protein expression level of HDAC3, Tip60, light chain 3 (LC3) in glioma samples by western blot
Our results showed that the anti-tumor activity of N25 in glioma cells is slightly stronger than Suberoylanilide hydroxamic acid (SAHA) both in vitro and in vivo
Summary
Glioma is both the most common and lethal primary brain tumor which occurs in adults and children [1, 2]. The median survival rate is only 13-16 months after standard therapy and more than 70% of glioblastoma patients die within two years of diagnosis [3, 4]. Development of novel therapeutic drugs and new treatment strategies is essential for improving glioblastoma survival. Epigenetic changes play a key role in the occurrence and development of cancer [5,6,7] and are a hot spot in international cancer research. Histone acetylation and deacetylation are important ways of epigenetic modifications [8]. Numerous studies have confirmed that various human cancers are associated with HDACs overexpression and that histone acetylation imbalance caused by enhanced intra-tumoral HDACs activity affects the occurrence and development of cancer [10,11,12].
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