Cellular Oncology group, Biodonostia Health Research Institute, San Sebastian, Spain.
Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), San Sebastian, Spain.
Cell Death Dis. 2020 Jun 2;11(6):417. doi: 10.1038/s41419-020-2586-x.
Histone deacetylase 6 (HDAC6) is an epigenetic modifier that is an attractive pharmacological target in cancer. In this work, we show that HDAC6 is elevated in glioblastoma, the most malignant and common brain tumor in adults, in which its high levels correlate with poor patient survival and is more abundant in glioma stem cell subpopulation. Moreover, we identified a new small-molecule inhibitor of HDAC6, which presents strong sensitivity for HDAC6 inhibition and exerts high cytotoxic activity, alone or in combination with temozolomide. It is also able to significantly reduce tumor growth in vivo. Transcriptomic analysis of patient-derived glioma stem cells revealed an increase in cell differentiation and cell death pathways, as well as a decrease in cell-cycle activity and cell division by the treatment with the compound. Finally, the comparison with a pan-HDAC inhibitor, Vorinostat (SAHA), or HDAC6-specific inhibitor, Tubastatin A, showed higher target specificity and antitumor activity of the new HDAC6 inhibitor. In conclusion, our data reveal the efficacy of a novel HDAC6 inhibitor in glioblastoma preclinical setting.
组蛋白去乙酰化酶 6（HDAC6）是一种表观遗传修饰物，是癌症中一种有吸引力的药物靶点。在这项工作中，我们表明 HDAC6 在神经胶质瘤中升高，神经胶质瘤是成人中最恶性和最常见的脑肿瘤，其高水平与患者生存不良相关，并且在神经胶质瘤干细胞亚群中更为丰富。此外，我们鉴定了一种新的 HDAC6 小分子抑制剂，它对 HDAC6 抑制具有很强的敏感性，并具有单独或与替莫唑胺联合的高细胞毒性活性。它还能够显著减少体内肿瘤生长。用该化合物处理患者来源的神经胶质瘤干细胞的转录组分析显示，细胞分化和细胞死亡途径增加，细胞周期活性和细胞分裂减少。最后，与泛 HDAC 抑制剂伏立诺他（SAHA）或 HDAC6 特异性抑制剂 Tubastatin A 的比较表明，新型 HDAC6 抑制剂具有更高的靶特异性和抗肿瘤活性。总之，我们的数据揭示了新型 HDAC6 抑制剂在神经胶质瘤临床前环境中的疗效。
