Ricolinostat (ACY-1215) suppresses proliferation and promotes apoptosis in esophageal squamous cell carcinoma via miR-30d/PI3K/AKT/mTOR and ERK pathways.
Ricolinostat (ACY-1215) suppresses proliferation and promotes apoptosis in esophageal squamous cell carcinoma via miR-30d/PI3K/AKT/mTOR and ERK pathways.
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DOI：
10.1038/s41419-018-0788-2
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发表时间：
2018-07-26
影响因子：
9
通讯作者：
Hu J
中科院分区：
文献类型：
--
作者：
Cao J;Lv W;Wang L;Xu J;Yuan P;Huang S;He Z;Hu J
Ricolinostat（ACY-1215）是一类选择性HDAC 6抑制剂，在各种癌症中单独或与其他药物联合显示出抗肿瘤作用。然而，其在食管癌中的疗效仍不清楚。在这项研究中，我们发现HDAC 6的高表达与食管鳞状细胞癌（ESCC）组织中的不良预后相关。ACY-1215能显著抑制食管鳞癌细胞增殖，并使细胞发生G2/M期阻滞和凋亡。我们进一步证明ACY-1215处理降低了PI 3 K、P-AKT、P-mTOR和P-ERK 1/2的表达，并增加了Ac-H3 K9和Ac-H4 K8的表达。此外，通过miRNA芯片和生物信息学分析，我们检测到ACY-1215促进miR-30 d的表达，PI 3 K调节亚基2（PIK 3R 2）是miR-30 d的直接靶点。抗miR-30 d部分挽救了ACY-1215处理引起的G2/M期阻滞和细胞凋亡。PI 3 K、P-AKT和P-mTOR表达的降低也被miR-30 d抑制剂部分逆转。此外，ACY-1215抑制ESCC增殖的作用在体内小鼠异种移植模型中得到验证。结论：ACY-1215通过miR-30 d/PI 3 K/AKT/mTOR和ERK通路抑制食管鳞癌细胞增殖并促进其凋亡，ACY-1215可能是一种有前景的抗食管鳞癌药物。
Ricolinostat (ACY-1215), a first-in-class selective HDAC6 inhibitor, exhibits antitumor effects alone or in combination with other drugs in various cancers. However, its efficacy in esophageal cancer remains unclear. In this study, we found that the high expression of HDAC6 was associated with poor prognosis in esophageal squamous cell carcinoma (ESCC) tissues. Then, we identified that ACY-1215 significantly inhibited cellular proliferation in ESCC, and caused G2/M phase arrest and apoptosis. We further demonstrated that ACY-1215 treatment reduced the expression of PI3K, P-AKT, P-mTOR, and P-ERK1/2 and increased that of Ac-H3K9 and Ac-H4K8. In addition, using miRNA microarray and bioinformatics analysis, we detected that ACY-1215 promoted miR-30d expression, and PI3K regulatory subunit 2 (PIK3R2) was a direct target of miR-30d. Anti-miR-30d partially rescued the G2/M phase arrest and apoptosis caused by ACY-1215 treatment. The reductions in PI3K, P-AKT, and P-mTOR expression were also partially reversed by miR-30d inhibitor. Furthermore, the effects of ACY-1215 inhibited ESCC proliferation were validated in a mouse xenograft model in vivo. In conclusion, our study showed that ACY-1215 suppressed proliferation and promoted apoptosis in ESCC via miR-30d/PI3K/AKT/mTOR and ERK pathways and that ACY-1215 may be a promising antitumor agent in ESCC.
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影响因子：
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作者：
Sibbesen NA;Kopp KL;Litvinov IV;Jønson L;Willerslev-Olsen A;Fredholm S;Petersen DL;Nastasi C;Krejsgaard T;Lindahl LM;Gniadecki R;Mongan NP;Sasseville D;Wasik MA;Iversen L;Bonefeld CM;Geisler C;Woetmann A;Odum N
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DOI：
10.1007/s10495-017-1364-4
发表时间：
2017-06
期刊：
Apoptosis : an international journal on programmed cell death
影响因子：
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作者：
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通讯作者：
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DOI：
10.1186/s13058-015-0658-0
发表时间：
2015-12-08
期刊：
Breast cancer research : BCR
影响因子：
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Silva J