Anhui Province Key Laboratory of Molecular Medicine, Anhui Provincial Hospital Affiliated to Anhui Medical University, Hefei, China.
Curr Mol Med. 2012 Mar;12(3):342-54. doi: 10.2174/156652412799218949.
Epigenetic silencing of the tumor suppressor gene, RARβ2, through histone deacetylation has been established as an important process of cervical carcinogenesis. This pivotal role has led to the suggestion that a combination of retinoids selective for RARβ2 with histone deacetylase (HDAC) inhibitors may have therapeutic potential. Valproic acid (VPA), a HDAC inhibitor, has a critical role in the regulation of gene expression through histone acetylation and causes transformed cells to undergo growth arrest, differentiation, and apoptosis. Therefore, we hypothesized that the combination of VPA and ATRA could restore RARβ2 expression, thus resulting in enhanced anti-neoplastic activity in cervical cancer. Here, we show that VPA combined with ATRA led to hyperacetylation of histone H3 and a significant alteration of gene expression in cervical cancer cells, including RARβ2 gene expression, which was upregulated 50- to 90-fold. The combination therapy effectively inhibited the growth of cervical cancer cells more than the single agent treatment both in vitro and in vivo. The additive effects were associated with a significant upregulation of p21(CIP1) and p53 as well as a pronounced decrease in p-Stat3. Furthermore, the combined treatment led to cell cycle arrest predominantly at the G1 phase, and it preferentially induced cell differentiation rather than apoptosis in cervical cancer cells. The differentiation program was determined by the presence of E-cadherinmediated adhesion and activation of the PI3K/Akt pathway. Taken together, these results provide new insight into the mechanisms of enhanced antitumor activity of the HDAC inhibitor and ATRA regimen, thus offering a new therapeutic strategy for cervical cancer patients.
肿瘤抑制基因 RARβ2 的表观遗传沉默通过组蛋白去乙酰化已被确立为宫颈癌发生的一个重要过程。这一关键作用导致人们提出这样的假设，即选择性针对 RARβ2 的维甲酸与组蛋白去乙酰化酶 (HDAC) 抑制剂的联合可能具有治疗潜力。组蛋白去乙酰化酶抑制剂丙戊酸 (VPA) 通过组蛋白乙酰化在基因表达调控中起着关键作用，并导致转化细胞生长停滞、分化和凋亡。因此，我们假设 VPA 和 ATRA 的联合使用可以恢复 RARβ2 的表达，从而导致宫颈癌的抗肿瘤活性增强。在这里，我们表明 VPA 与 ATRA 的联合使用导致组蛋白 H3 的过度乙酰化，以及宫颈癌细胞中基因表达的显著改变，包括 RARβ2 基因表达上调 50-90 倍。联合治疗在体外和体内都比单一药物治疗更有效地抑制宫颈癌细胞的生长。这种增效作用与 p21(CIP1) 和 p53 的显著上调以及 p-Stat3 的明显下降有关。此外，联合治疗主要导致细胞周期停滞在 G1 期，并在宫颈癌细胞中优先诱导细胞分化而不是凋亡。分化程序由 E-钙粘蛋白介导的粘附和 PI3K/Akt 途径的激活决定。总之，这些结果为增强 HDAC 抑制剂和 ATRA 方案的抗肿瘤活性的机制提供了新的见解，为宫颈癌患者提供了一种新的治疗策略。
