Kang Sisi, Wang Zhuo, Li Bin, Gao Xiujuan, He Wenjuan, Cao Sisi, Cai Yue, Chen Hui
Pharmazie. 2019 Mar 1;74(3):163-167. doi: 10.1691/ph.2019.8838.
The natural phytoalexin resveratrol (RES) has exhibited excellent anti-tumor effects on a variety of tumors including malignant melanoma. However, its specific mechanism of anti-melanoma needs to be further explored. It has been reported, that the expression of tumor suppressor gene RUNX3 was lost or substantially decreased in melanoma. Whether RES exerts its anti-tumor effect by regulating the expression of RUNX3 gene in melanoma is worthy of study. In the present study, we found the RUNX3 promoter is hypermethylated and the expression of RUNX3 mRNA and protein are absent in melanoma cells B16F10. After intervention with RES, promoter hypermethylation of RUNX3 in B16F10 cells could be significantly decreased and mRNA and protein expression of it was upregulated in a dose-dependent manner. We further investigated the effects of RES on B16F10 xenograft models. The intervention of RES and treatment of melanoma positive drug dacarbazine (DTIC) both could significantly inhibit tumor growth in xenograft mice, but only RES could upregulate the expression of RUNX3 mRNA and protein in peripheral blood and tumor tissues. Therefore, the upregulation of mRNA and protein expression of RUNX3 resulting from promoter demethylation might be one of the mechanisms of RES inhibiting melanoma. This research has revealed a novel mechanism for RES against melanoma from the epigenetic perspective, which is helpful to improve the understanding of the anti-tumor mechanism of RES and provide new insights for the treatment of melanoma.
天然植物抗毒素白藜芦醇（RES）已对包括恶性黑色素瘤在内的多种肿瘤表现出优异的抗肿瘤作用。然而，其抗黑色素瘤的具体机制有待进一步探究。据报道，肿瘤抑制基因RUNX3在黑色素瘤中表达缺失或显著降低。RES是否通过调节黑色素瘤中RUNX3基因的表达发挥其抗肿瘤作用值得研究。在本研究中，我们发现黑色素瘤细胞B16F10中RUNX3启动子发生高甲基化，且不存在RUNX3 mRNA和蛋白的表达。RES干预后，B16F10细胞中RUNX3的启动子高甲基化可显著降低，其mRNA和蛋白表达呈剂量依赖性上调。我们进一步研究了RES对B16F10异种移植模型的影响。RES干预和黑色素瘤阳性药物达卡巴嗪（DTIC）治疗均能显著抑制异种移植小鼠的肿瘤生长，但只有RES能上调外周血和肿瘤组织中RUNX3 mRNA和蛋白的表达。因此，启动子去甲基化导致RUNX3 mRNA和蛋白表达上调可能是RES抑制黑色素瘤的机制之一。本研究从表观遗传学角度揭示了RES抗黑色素瘤的新机制，有助于增进对RES抗肿瘤机制的理解，并为黑色素瘤的治疗提供新的思路。
