Key Laboratory of Genomics and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
EMBO Rep. 2018 Aug;19(8). doi: 10.15252/embr.201745401. Epub 2018 Jun 28.
Loss of 5-hydroxymethylcytosine (5hmC) occurs frequently in a wide variety of tumours, including clear-cell renal cell carcinoma (ccRCC). It remains unknown, however, whether the restoration of 5hmC patterns in tumours could have therapeutic efficacy. Here, we used sodium L-ascorbate (vitamin C, AsANa) and the oxidation-resistant form L-ascorbic acid 2-phosphate sesquimagnesium (APM) for the restoration of 5hmC patterns in ccRCC cells. At physiological concentrations, both show anti-tumour efficacy during long-term treatment Strikingly, global 5hmC patterns in ccRCC cells after treatment resemble those of normal kidney tissue, which is observed also in treated xenograft tumours, and in primary cells from a ccRCC patient. Further, RNA-seq data show that long-term treatment with vitamin C changes the transcriptome of ccRCC cells. Finally, APM treatment induces less non-specific cell damage and shows increased stability in mouse plasma compared to AsANa. Taken together, our study provides proof of concept for an epigenetic differentiation therapy of ccRCC with vitamin C, especially APM, at low doses by 5hmC reprogramming.
5-羟甲基胞嘧啶（5hmC）的丢失在多种肿瘤中经常发生，包括透明细胞肾细胞癌（ccRCC）。然而，尚不清楚肿瘤中 5hmC 模式的恢复是否具有治疗效果。在这里，我们使用抗坏血酸钠（维生素 C，AsANa）和氧化抗性形式的 L-抗坏血酸 2-磷酸半镁（APM）来恢复 ccRCC 细胞中的 5hmC 模式。在生理浓度下，两者在长期治疗过程中均显示出抗肿瘤功效。引人注目的是，ccRCC 细胞经过治疗后的全局 5hmC 模式类似于正常肾脏组织，这也观察到在治疗的异种移植肿瘤和 ccRCC 患者的原代细胞中。此外，RNA-seq 数据显示，维生素 C 的长期治疗会改变 ccRCC 细胞的转录组。最后，与 AsANa 相比，APM 治疗在小鼠血浆中引起的非特异性细胞损伤较小，且稳定性更高。综上所述，我们的研究提供了使用维生素 C（特别是 APM）通过 5hmC 重编程进行 ccRCC 表观遗传分化治疗的概念验证，其剂量较低。
