Hao Zhen-Feng, Su You-Ming, Wang Cong-min, Yang Rong-Ya
Institute of Skin Damage and Repair, General Hospital of Beijing Region of PLA, Beijing, 100700, China.
Tumour Biol. 2015 Mar;36(3):1471-6. doi: 10.1007/s13277-014-2618-1. Epub 2014 Nov 5.
Inhibition of histone deacetylase (HDAC) activity by HDAC inhibitors (HDACis) results in cancer cell growth inhibition, and HDACis have been revealed as potential anti-skin cancer agents. p21 is a cyclin-dependent kinase inhibitor and an essential regulator of growth inhibition. Recently, we reported that activating transcription factor 3 (ATF3) could significantly promote skin cancer cell growth. This study explored the relationship between ATF3 and HDACi-induced growth inhibition of epidermoid carcinoma cells. We found that trichostatin A (TSA) treatment inhibited cell growth in A431 epidermoid carcinoma cells in a dose-dependent manner. Simultaneously, p21 and ATF3 expression levels were upregulated and downregulated upon TSA stimulation, respectively. ATF3 overexpression promoted cell growth and downregulated p21 expression. In contrast, ATF3 depletion resulted in cell growth reduction and p21 transcriptional upregulation. More importantly, ATF3 overexpression partially antagonized TSA-induced growth inhibition and p21 activation. Collectively, these data demonstrate that ATF3 acts as an essential negative regulator of TSA-induced cell growth inhibition through interfering with TSA-induced p21 activation.
组蛋白去乙酰化酶抑制剂（HDACis）对组蛋白去乙酰化酶（HDAC）活性的抑制作用会导致癌细胞生长受到抑制，并且HDACis已被证实是潜在的抗皮肤癌药物。p21是一种细胞周期蛋白依赖性激酶抑制剂，也是生长抑制的关键调节因子。最近，我们报道激活转录因子3（ATF3）可显著促进皮肤癌细胞的生长。本研究探讨了ATF3与HDACi诱导的表皮样癌细胞生长抑制之间的关系。我们发现曲古抑菌素A（TSA）处理以剂量依赖性方式抑制A431表皮样癌细胞的生长。同时，在TSA刺激后，p21和ATF3的表达水平分别上调和下调。ATF3过表达促进细胞生长并下调p21表达。相反，ATF3缺失导致细胞生长减少和p21转录上调。更重要的是，ATF3过表达部分拮抗TSA诱导的生长抑制和p21激活。总的来说，这些数据表明ATF3通过干扰TSA诱导的p21激活，作为TSA诱导的细胞生长抑制的重要负调节因子。
