Departments of Dermatology, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
Melanoma Res. 2013 Jun;23(3):213-7. doi: 10.1097/CMR.0b013e328361056d.
The tumor suppressor p53 plays a central role in preventing tumor development by promoting transcription of genes that stall cell cycle and induce cell death. Although the majority of melanomas express wild-type p53, the molecular mechanisms that impede its activation remain unclear. We previously reported that the SUMO E3 ligase PIASy and the histone acetyltransferase Tip60 signaling cascade promote p53-dependent autophagy and apoptosis. We hypothesized that impairment in this signaling attenuates p53, thus disabling its apoptotic function in melanoma. Here, we show that human melanoma patient samples and cell lines maintain p53 expression but PIASy and/or Tip60 are frequently lost. We observed dysregulation of Tip60-mediated p53 transcription program in melanoma cell lines. Reconstitution of PIASy and Tip60 in melanoma cells increased genotoxic stress-induced apoptosis. Our study provides a clinical link of how sumoylation signaling may activate p53-mediated cell death in melanoma.
肿瘤抑制因子 p53 通过促进细胞周期停滞和诱导细胞死亡的基因转录，在预防肿瘤发生中发挥核心作用。尽管大多数黑色素瘤表达野生型 p53，但阻碍其激活的分子机制仍不清楚。我们之前报道称，SUMO E3 连接酶 PIASy 和组蛋白乙酰转移酶 Tip60 信号级联促进 p53 依赖性自噬和细胞凋亡。我们假设这种信号的损伤会削弱 p53，从而使其在黑色素瘤中的凋亡功能失活。在这里，我们展示了人类黑色素瘤患者样本和细胞系保持 p53 表达，但 PIASy 和/或 Tip60 经常丢失。我们观察到黑色素瘤细胞系中 Tip60 介导的 p53 转录程序失调。在黑色素瘤细胞中重建 PIASy 和 Tip60 会增加遗传毒性应激诱导的细胞凋亡。我们的研究提供了一个临床联系，说明 SUMO 信号如何在黑色素瘤中激活 p53 介导的细胞死亡。
