From the Departments of Medical Oncology.
Hematology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Pancreas. 2020 Jan;49(1):135-142. doi: 10.1097/MPA.0000000000001462.
Pancreatic cancer (PC) is highly aggressive with multiple oncogenic mutations. The efficacy of current chemotherapy is poor, and new therapeutic targets are needed. The forkhead box (FOX) proteins are multidirectional transcriptional factors strongly implicated in malignancies. Their expression is consistently suppressed by several oncogenic pathways such as PI3K/AKT signaling activated in PC. A recent study showed that class IIa histone deacetylases (HDAC) can act as a transcriptional suppressor. In this study, we hypothesized that HDAC class IIa inhibition would upregulate FOXO3a expression, thereby inducing its transcription-dependent antitumor effects.
We confirmed the change of FOXO3a expression and the effect of the cell growth inhibition by HDAC class IIa inhibition in AsPC-1 cells. Because FOXO3a is subject to ubiquitylation-mediated proteasome degradation, we examined the synergistic activation of FOXO3a by HDAC class IIa selective inhibitor TMP269 combined with proteasome inhibitor carfilzomib.
We observed that TMP269 induced FOXO3a expression in a dose-dependent manner and inhibited cell growth in AsPC-1 cells. G1/S arrest was observed. FOXO3a expression was further increased and cell growth inhibition was dramatically enhanced by TMP269 combined with carfilzomib.
Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC.
胰腺癌（PC）具有高度侵袭性和多种致癌突变。目前化疗的疗效不佳，需要新的治疗靶点。叉头框（FOX）蛋白是多向转录因子，强烈参与恶性肿瘤的发生。它们的表达被多种致癌途径持续抑制，如在 PC 中激活的 PI3K/AKT 信号通路。最近的一项研究表明，Ⅱa 类组蛋白去乙酰化酶（HDAC）可以作为转录抑制因子。在本研究中，我们假设 HDAC Ⅱa 抑制会上调 FOXO3a 的表达，从而诱导其依赖转录的抗肿瘤作用。
我们在 AsPC-1 细胞中证实了 HDAC Ⅱa 抑制对 FOXO3a 表达的改变和对细胞生长抑制的影响。由于 FOXO3a 受到泛素化介导的蛋白酶体降解，我们检查了 HDAC Ⅱa 选择性抑制剂 TMP269 与蛋白酶体抑制剂卡非佐米联合使用对 FOXO3a 的协同激活作用。
我们观察到 TMP269 以剂量依赖性方式诱导 FOXO3a 表达，并抑制 AsPC-1 细胞的生长。观察到 G1/S 期阻滞。TMP269 与卡非佐米联合使用进一步增加 FOXO3a 表达并显著增强细胞生长抑制。
双重抑制Ⅱa 类 HDAC 和蛋白酶体可能是一种有前途的新策略，可以调节 FOXO3a 活性对抗 PC。
