Nevada Cancer Institute, Las Vegas, NV 89135, USA.
Biochem Biophys Res Commun. 2011 Apr 8;407(2):271-6. doi: 10.1016/j.bbrc.2011.02.008.
Resveratrol (3,4',5-trihydroxy-trans-stilbene), a polyphenol naturally occurring in grapes and other plants, has cancer chemo-preventive effects and therapeutic potential. Although resveratrol modulates multiple pathways in tumor cells, how resveratrol or its affected pathways converge on chromatin to mediate its effects is not known. Using glioma cells as a model, we showed here that resveratrol inhibited cell proliferation and induced cellular hypertrophy by transforming spindle-shaped cells to enlarged, irregular and flatten-shaped ones. We further showed that resveratrol-induced hypertrophic cells expressed senescence-associated-β-galactosidase, suggesting that resveratrol-induced cellular senescence in glioma cells. Consistent with these observations, we demonstrated that resveratrol inhibited clonogenic efficiencies in vitro and tumor growth in a xenograft model. Furthermore, we found that acute treatment of resveratrol inhibited mono-ubiquitination of histone H2B at K120 (uH2B) in breast, prostate, pancreatic, lung, brain tumor cells as well as primary human cells. Chronic treatment with low doses of resveratrol also inhibited uH2B in the resveratrol-induced senescent glioma cells. Moreover, we showed that depletion of RNF20, a ubiquitin ligase of histone H2B, inhibited uH2B and induced cellular senescence in glioma cells in vitro, thereby recapitulated the effects of resveratrol. Taken together, our results suggest that uH2B is a novel direct or indirect chromatin target of resveratrol and RNF20 plays an important role in inhibiting cellular senescence programs that are intact in glioma cells.
白藜芦醇（3,4',5-三羟基反式-二苯乙烯），一种天然存在于葡萄和其他植物中的多酚，具有抗癌化学预防作用和治疗潜力。尽管白藜芦醇调节肿瘤细胞中的多种途径，但白藜芦醇或其受影响的途径如何汇聚到染色质上以介导其作用尚不清楚。在这里，我们使用神经胶质瘤细胞作为模型，表明白藜芦醇通过将纺锤形细胞转化为增大、不规则和平坦形状的细胞来抑制细胞增殖并诱导细胞肥大。我们进一步表明，白藜芦醇诱导的肥大细胞表达衰老相关的β-半乳糖苷酶，提示白藜芦醇诱导神经胶质瘤细胞发生细胞衰老。与这些观察结果一致，我们证明白藜芦醇抑制了体外克隆形成效率和异种移植模型中的肿瘤生长。此外，我们发现白藜芦醇的急性处理抑制了乳腺癌、前列腺癌、胰腺癌、肺癌、脑肿瘤细胞以及原代人类细胞中单泛素化组蛋白 H2B 赖氨酸 120（uH2B）。低剂量白藜芦醇的慢性处理也抑制了白藜芦醇诱导的衰老神经胶质瘤细胞中的 uH2B。此外，我们表明，组蛋白 H2B 的泛素连接酶 RNF20 的耗竭抑制了 uH2B 并诱导了体外神经胶质瘤细胞的衰老，从而再现了白藜芦醇的作用。总之，我们的结果表明，uH2B 是白藜芦醇的一种新型直接或间接染色质靶标，RNF20 在抑制神经胶质瘤细胞中完整的细胞衰老程序中发挥重要作用。
