Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Oncol. 2010 Apr;36(4):999-1005. doi: 10.3892/ijo_00000580.
Inactivation of tumor suppressor genes is a major contributing alteration in the initiation or progression of cancer. The human tumor suppressor gene DLC1 (deleted in liver cancer 1) is frequently downregulated or silenced in multiple cancers, predominantly by epigenetic mechanisms. With the current considerable interest and progress in epigenetic therapy, a number of promising antineoplastic agents, particularly histone deacetylase (HDAC) inhibitors, have been developed and used successfully in clinical trials. Both DLC1 and HDAC inhibitors exert antineoplastic functions, and their combined action could be exploited for a more effective cancer therapy. To evaluate the potential benefits of this approach, we examined the antineoplastic effects of adenoviral (Ad)-DLC1-mediated transduction and exposure to suberoylanilide hydroxamic acid (SAHA), a powerful HDAC inhibitor, in two human cancer cell lines that lack intrinsic DLC1 expression, 22Rv1 prostate cancer cells and 7703K human hepatocellular carcinoma cells. Consistent with the oncosuppressive function of DLC1 in several cancers, including prostate and liver cancer, transduction of 22Rv1 and 7703K cells with an Ad-DLC1 expression vector resulted in alterations of cell morphology, induction of apoptosis, and inhibition of cell proliferation, migration, and anchorage-independent growth. A low concentration of SAHA (5 microM) efficiently restored the expression of DLC1 in 22Rv1 cells that lack DLC1 expression due to histone deacetylation but had a minimal effect in 7703K cells in which silencing of the DLC1 gene is due mainly to promoter hypermethylation. Regardless of the epigenetic mechanism of DLC1 inactivation, SAHA treatment of DLC1-transduced cells had a synergistic inhibitory effect on tumor cell proliferation and tumorigenesis in both cell lines. In 22Rv1 cells, this combination regimen nearly abolished the formation of colonies in semisolid media as a measure of tumorigenicity in vitro. Current in vitro results validate this protocol as a potentially new therapeutic option in certain cancers.
肿瘤抑制基因失活是癌症发生或进展的主要原因之一。人类肿瘤抑制基因 DLC1（肝癌缺失基因 1）在多种癌症中经常下调或沉默，主要是通过表观遗传机制。随着当前对表观遗传治疗的极大兴趣和进展，已经开发并成功地在临床试验中使用了许多有前途的抗肿瘤药物，特别是组蛋白去乙酰化酶（HDAC）抑制剂。DLC1 和 HDAC 抑制剂都具有抗肿瘤功能，它们的联合作用可用于更有效的癌症治疗。为了评估这种方法的潜在益处，我们研究了腺病毒（Ad）-DLC1 介导的转导和暴露于琥珀酰亚胺基羟酸（SAHA）对两种缺乏内在 DLC1 表达的人类癌细胞系（前列腺癌 22Rv1 细胞和肝癌 7703K 细胞）的抗肿瘤作用，SAHA 是一种强大的 HDAC 抑制剂。与 DLC1 在包括前列腺癌和肝癌在内的多种癌症中的抑癌功能一致，转导 22Rv1 和 7703K 细胞的 Ad-DLC1 表达载体导致细胞形态改变、诱导细胞凋亡以及抑制细胞增殖、迁移和非锚定依赖性生长。低浓度的 SAHA（5 μM）有效地恢复了由于组蛋白去乙酰化而缺乏 DLC1 表达的 22Rv1 细胞中 DLC1 的表达，但对主要由于启动子甲基化沉默 DLC1 基因的 7703K 细胞的影响最小。无论 DLC1 失活的表观遗传机制如何，SAHA 处理 DLC1 转导的细胞对两种细胞系的肿瘤细胞增殖和肿瘤发生均具有协同抑制作用。在 22Rv1 细胞中，这种联合方案几乎消除了半固体培养基中集落的形成，作为体外致瘤性的衡量标准。目前的体外结果验证了该方案作为某些癌症的潜在新治疗选择。
