FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells
FOXO3a Activation by HDAC Class IIa Inhibition Induces Cell Cycle Arrest in Pancreatic Cancer Cells
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DOI：
10.1097/mpa.0000000000001462
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发表时间：
2020-01-01
期刊：
影响因子：
2.9
通讯作者：
Kato, Junji
中科院分区：
文献类型：
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作者：
Usami, Makoto;Kikuchi, Shohei;Kato, Junji
目的胰腺癌（PC）是一种高度侵袭性的肿瘤，具有多种癌基因突变。目前的化疗效果不佳，需要新的治疗靶点。叉头盒（FOX）蛋白是与恶性肿瘤密切相关的多方向转录因子。它们的表达受到几种致癌途径如PC中激活的PI 3 K/AKT信号转导的一致抑制。最近的一项研究表明，IIa类组蛋白去乙酰化酶（HDAC）可以作为一个转录抑制因子。在这项研究中，我们假设HDAC IIa类抑制将上调FOXO 3a表达，从而诱导其转录依赖性抗肿瘤作用。方法通过观察HDAC Ⅱ a抑制剂对AsPC-1细胞FOXO 3a表达的影响及对细胞生长的抑制作用，探讨HDAC Ⅱ a抑制剂对AsPC-1细胞FOXO 3a表达的影响。由于FOXO 3a是受泛素化介导的蛋白酶体降解，我们研究了HDAC IIa类选择性抑制剂TMP 269与蛋白酶体抑制剂卡非佐米联合对FOXO 3a的协同激活作用。结果TMP 269可剂量依赖性地诱导AsPC-1细胞FOXO 3a的表达，并抑制AsPC-1细胞的生长。G1/S期阻滞。TMP 269与卡非佐米联合使用可进一步增加FOXO 3a表达，并显著增强细胞生长抑制作用。结论IIa类HDACs和蛋白酶体的双重抑制可能是改变FOXO 3a抗PC活性的新策略。
Objectives 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. Methods 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. Results 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. Conclusions Dual inhibition of class IIa HDACs and proteasome could be a promising new strategy for modifying FOXO3a activity against PC.