Preclinical evaluation of combined antineoplastic effect of DLC1 tumor suppressor protein and suberoylanilide hydroxamic acid on prostate cancer cells.
Preclinical evaluation of combined antineoplastic effect of DLC1 tumor suppressor protein and suberoylanilide hydroxamic acid on prostate cancer cells.
复制标题
DOI：
10.1016/j.bbrc.2012.02.158
复制
发表时间：
2012-04-06
影响因子：
3.1
通讯作者：
Popescu NC
中科院分区：
文献类型：
--
作者：
Zhou X;Yang XY;Popescu NC
肝癌中的缺失（dcl1）是多种癌症中的肿瘤抑制基因，在原发性前列腺癌（pca）中通过表观遗传机制反复下调或失活。在这项研究中，我们检测了三种低或检测不到DLC1表达的PCA细胞系（LNCaP、其衍生物C4-2B-2和22Rv1）中DLC1启动子区域的甲基化和乙酰化谱。两种组蛋白去乙酰化酶抑制剂（HDAC），亚eroylanilide羟肟酸（SAHA）和trichostatin A （TSA）在所有三个品系中诱导DLC1启动子的组蛋白乙酰化。LNCaP和C4-2B-2细胞中检测到DLC1启动子甲基化和去乙酰化，而在22rv1细胞中，DLC1启动子被去乙酰化沉默。SAHA或TSA有效地增加了所有细胞系，尤其是22Rv1细胞的DLC1表达，并通过相同的Sp1位点激活了DLC1启动子。选择22Rv1细胞系，评价DLC1转导与SAHA联合治疗对胸腺小鼠肿瘤生长的影响。与对照组相比，DLC1转导和SAHA暴露单独减少了75-80%的肿瘤大小，并且几乎完全抑制了肿瘤的生长。抗肿瘤作用与诱导细胞凋亡和抑制RhoA活性有关。单独SAHA可显著降低RhoA活性，表明该RhoGTPase是SAHA的靶标。这些结果是通过可靠的临床前体内试验获得的，预测靶向控制dcl1功能的途径和HDAC抑制剂的联合治疗药物可能有益于前列腺癌的治疗。
Deleted in liver cancer (DLC1), a tumor suppressor gene in multiple cancers, is recurrently down regulated or inactivated by epigenetic mechanisms in primary prostate carcinomas (PCAs). In this study the methylation and acetylation profile of the DLC1 promoter region was examined in three PCA cell lines with low or undetectable DLC1 expression: LNCaP, its derivative C4-2B-2, and 22Rv1. Two histone deacetylase inhibitors (HDAC), suberoylanilide hydroxamic acid (SAHA) and trichostatin A (TSA) induced histone acetylation of the DLC1 promoter in all three lines. DLC1 promoter methylation and deacetylation were detected in LNCaP and C4-2B-2 cells while in 22Rv1cells DLC1 is silenced by deacetylation. Treatment with SAHA or TSA efficiently increased DLC1 expression in all lines, particularly in 22Rv1 cells, and activated the DLC1 promoter through the same Sp1 sites. The 22Rv1 cell line was selected to evaluate the efficacy of combined DLC1 transduction and SAHA treatment on tumor growth in athymic mice. Individually, DLC1 transduction and SAHA exposure reduced the tumor size by 75–80% compared to controls and in combination almost completely inhibited tumor growth. The antitumor effect was associated with the induction of apoptosis and inhibition of RhoA activity. SAHA alone significantly reduced RhoA activity, showing that this RhoGTPase is a target for SAHA. These results, obtained with a reliable preclinical in vivo test, predict that combined therapeutic agents targeting the pathways governing DLC1 function and HDAC inhibitors may be beneficial in management of prostate cancer.
登录
查看更多内容
影响因子：
10.5
作者：
Lahoz, Aurelia;Hall, Alan
通讯作者：
Hall, Alan
影响因子：
12.8
作者：
Kim, Tai Young;Kim, In Sook;Bang, Yung-Jue
通讯作者：
Bang, Yung-Jue
DOI：
10.1038/nrc2960
发表时间：
2010-12
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
影响因子：
5.2
作者：
Zhou, Xiaoling;Yang, Xu-Yu;Popescu, Nicholas C.
通讯作者：
Popescu, Nicholas C.
影响因子：
11.5
作者：
Guan, M;Zhou, XL;Popescu, NC
通讯作者：
Popescu, NC