Department of Medical Oncology, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Leukemia. 2015 Sep;29(9):1918-27. doi: 10.1038/leu.2015.83. Epub 2015 Mar 24.
Histone deacetylase (HDAC) inhibitors have been extensively investigated as therapeutic agents in cancer. However, the biological role of class IIa HDACs (HDAC4, 5, 7 and 9) in cancer cells, including multiple myeloma (MM), remains unclear. Recent studies show HDAC4 interacts with activating transcription factor 4 (ATF4) and inhibits activation of endoplasmic reticulum (ER) stress-associated proapoptotic transcription factor C/EBP homologous protein (CHOP). In this study, we hypothesized that HDAC4 knockdown and/or inhibition could enhance apoptosis in MM cells under ER stress condition by upregulating ATF4, followed by CHOP. HDAC4 knockdown showed modest cell growth inhibition; however, it markedly enhanced cytotoxicity induced by either tunicamycin or carfilzomib (CFZ), associated with upregulating ATF4 and CHOP. For pharmacological inhibition of HDAC4, we employed a novel and selective class IIa HDAC inhibitor TMP269, alone and in combination with CFZ. As with HDAC4 knockdown, TMP269 significantly enhanced cytotoxicity induced by CFZ in MM cell lines, upregulating ATF4 and CHOP and inducing apoptosis. Conversely, enhanced cytotoxicity was abrogated by ATF4 knockdown, confirming that ATF4 has a pivotal role mediating cytotoxicity in this setting. These results provide the rationale for novel treatment strategies combining class IIa HDAC inhibitors with ER stressors, including proteasome inhibitors, to improve patient outcome in MM.
组蛋白去乙酰化酶（HDAC）抑制剂已被广泛研究作为癌症的治疗药物。然而，IIa 类 HDAC（HDAC4、5、7 和 9）在癌细胞中的生物学作用，包括多发性骨髓瘤（MM），仍不清楚。最近的研究表明，HDAC4 与激活转录因子 4（ATF4）相互作用，并抑制内质网（ER）应激相关促凋亡转录因子 C/EBP 同源蛋白（CHOP）的激活。在这项研究中，我们假设 HDAC4 敲低和/或抑制通过上调 ATF4 随后上调 CHOP，可增强 ER 应激条件下 MM 细胞中的细胞凋亡。HDAC4 敲低显示出适度的细胞生长抑制；然而，它显著增强了由衣霉素或卡非佐米（CFZ）诱导的细胞毒性，与上调 ATF4 和 CHOP 相关。为了抑制 HDAC4 的药理学作用，我们使用了一种新型和选择性的 IIa 类 HDAC 抑制剂 TMP269，单独使用或与 CFZ 联合使用。与 HDAC4 敲低一样，TMP269 显著增强了 MM 细胞系中 CFZ 诱导的细胞毒性，上调了 ATF4 和 CHOP，并诱导了细胞凋亡。相反，ATF4 敲低消除了增强的细胞毒性，证实 ATF4 在这种情况下介导细胞毒性起着关键作用。这些结果为联合使用 IIa 类 HDAC 抑制剂和 ER 应激剂（包括蛋白酶体抑制剂）的新型治疗策略提供了依据，以改善 MM 患者的预后。
