Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan.
Cancer Sci. 2018 Aug;109(8):2520-2531. doi: 10.1111/cas.13700. Epub 2018 Jul 23.
Current therapies for pancreatic ductal cancer (PDAC) do not sufficiently control distant metastasis. Thus, new therapeutic targets are urgently needed. Numerous studies have suggested that the epithelial-mesenchymal transition (EMT) is pivotal for metastasis of carcinomas. The fact that the EMT is reversible suggests the possibility that it is induced by an epigenetic mechanism. In this study, we aimed to investigate the role of histone deacetylase 1 (HDAC1), which is an epigenetic mechanism on distant metastasis of PDAC. We investigated the HDAC1 expression in 103 resected PDAC specimens obtained from patients who were treated with/without preoperative therapy using immunohistochemistry. To validate the findings in the clinical samples, we evaluated the HDAC1 activity, the EMT-associated genes and the migration/invasion ability in vitro, and performed an HDAC1 inhibitor assay. The high expression of HDAC1 in clinical samples was significantly associated with poor progression-free survival, especially distant metastasis-free survival. In vitro, HDAC1 inhibitors decreased the invasion ability and reversed the EMT change; the only factor to show a concomitant decrease was the expression of SNAIL. We confirmed that the HDAC1 expression was associated with the SNAIL expression in clinical samples. Moreover, the resistant cells and parental cells did not show any significant differences in the expression of HDAC1; this was consistent with the finding that preoperative therapy did not alter the HDAC1 expression in clinical samples. The targeting of HDAC1, which could suppress metastasis by inhibiting the EMT, is a promising treatment option for PDAC.
目前针对胰腺导管腺癌 (PDAC) 的治疗方法并不能充分控制远处转移。因此，迫切需要新的治疗靶点。大量研究表明上皮间质转化 (EMT) 是癌转移的关键。EMT 是可逆的这一事实表明它可能是由表观遗传机制诱导的。在这项研究中，我们旨在研究组蛋白去乙酰化酶 1 (HDAC1) 在 PDAC 远处转移中的作用，因为它是一种表观遗传机制。我们使用免疫组织化学法检测了 103 例接受/未接受术前治疗的 PDAC 患者手术切除标本中 HDAC1 的表达。为了验证临床样本中的发现，我们在体外评估了 HDAC1 活性、EMT 相关基因和迁移/侵袭能力，并进行了 HDAC1 抑制剂测定。临床样本中 HDAC1 的高表达与无进展生存期，特别是无远处转移生存期不良显著相关。在体外，HDAC1 抑制剂降低了侵袭能力并逆转了 EMT 变化；唯一表现出伴随下降的是 SNAIL 的表达。我们证实 HDAC1 的表达与临床样本中 SNAIL 的表达相关。此外，耐药细胞和亲本细胞在 HDAC1 的表达上没有任何显著差异；这与术前治疗未改变临床样本中 HDAC1 表达的发现一致。靶向 HDAC1 通过抑制 EMT 抑制转移是 PDAC 有前途的治疗选择。
