C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer.
C646 inhibits G2/M cell cycle-related proteins and potentiates anti-tumor effects in pancreatic cancer.
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DOI：
10.1038/s41598-021-89530-8
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发表时间：
2021-05-12
影响因子：
4.6
通讯作者：
Tanabe M
中科院分区：
文献类型：
--
作者：
Ono H;Kato T;Murase Y;Nakamura Y;Ishikawa Y;Watanabe S;Akahoshi K;Ogura T;Ogawa K;Ban D;Kudo A;Akiyama Y;Tanaka S;Ito H;Tanabe M
组蛋白乙酰基转移酶（HAT）的活性在与组蛋白脱乙酰基转移酶（HDAC）合作的表观遗传修饰中起核心作用。控制表观遗传修饰的这种酶机制的故障可能与致癌和肿瘤进展有关。然而，在胰腺癌中，HAT活性和组蛋白乙酰化的临床相关性仍不清楚。我们发现H3乙酰化在所有胰腺癌患者中表达，表明H3乙酰化在胰腺癌细胞中可能是必需的。我们还发现，HAT抑制剂C646通过抑制细胞增殖和细胞周期进展，同时抑制乙酰化H3 K9和H3 K27的表达，增强了体外抗肿瘤作用。C646或p300和CBP（CREB结合蛋白）特异性siRNA处理抑制G2/M期细胞周期调控蛋白cyclin B1和CDK 1（细胞周期蛋白依赖性激酶1）的转录。C646处理还在异种移植小鼠模型中抑制体内肿瘤生长。C646可能是胰腺癌的有效治疗药物。基于组蛋白H3乙酰化水平的胰腺癌的表观遗传状态可能影响患者的生存率。根据H3 K27乙酰化的表观遗传分层可能有助于预测疾病预后以及C646在胰腺癌中的治疗效果。
The activity of histone acetyltransferases (HATs) plays a central role in an epigenetic modification in cooperation with HDACs (histone deacetyl transferases). It is likely that malfunction of this enzymatic machinery controlling epigenetic modification is relevant to carcinogenesis and tumor progression. However, in pancreatic cancer, the clinical relevance of HAT activity and histone acetylation has remained unclear. We identified that H3 acetylation was expressed in all pancreatic cancer patients, indicating that H3 acetylation may be essential in pancreatic cancer cells. We also found that the HAT inhibitor C646 augmented anti-tumor effects in vitro by inhibiting cell proliferation and cell cycle progression concomitantly with suppression of acetylated H3K9 and H3K27 expression. C646 or p300 and CBP (CREB-binding protein)-specific siRNA treatment inhibited the transcription of the G2/M cell cycle regulatory proteins cyclin B1 and CDK1 (cyclin-dependent kinase 1). C646 treatment also inhibited tumor growth in vivo in a xenograft mouse model. C646 could be an effective therapeutic agent for pancreatic cancer. The epigenetic status of pancreatic cancers based on their level of histone H3 acetylation may influence patient survival. Epigenetic stratification according to H3K27 acetylation could be useful for predicting disease prognosis as well as the therapeutic efficacy of C646 in pancreatic cancer.
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影响因子：
10.5
作者：
Morgan MA;Shilatifard A
通讯作者：
Shilatifard A
影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
64.8
作者：
Heintzman, Nathaniel D.;Hon, Gary C.;Hawkins, R. David;Kheradpour, Pouya;Stark, Alexander;Harp, Lindsey F.;Ye, Zhen;Lee, Leonard K.;Stuart, Rhona K.;Ching, Christina W.;Ching, Keith A.;Antosiewicz-Bourget, Jessica E.;Liu, Hui;Zhang, Xinmin;Green, Roland D.;Lobanenkov, Victor V.;Stewart, Ron;Thomson, James A.;Crawford, Gregory E.;Kellis, Manolis;Ren, Bing
通讯作者：
Ren, Bing
影响因子：
2.5
作者：
Gerrard, Diana L.;Boyd, Joseph R.;Frietze, Seth
通讯作者：
Frietze, Seth
影响因子：
1.6
作者：
Kishimoto T
通讯作者：
Kishimoto T