Vitamin C, also known as Ascorbic acid (AsA), is one of the important water soluble vitamins in daily life. It plays essential role in collagen synthesis, carnitine and neurotransmitters biosynthesis. High dose AsA was first discovered in 17th century as an anti-cancer drug. Because of the instability and the toxicity effect, high dose AsA in cancer treatment still has ambiguity claims and controversies. Recently, a research named “Restoration of 5-hydroxymethylcytosine by ascorbate reduces kidney tumor growth” was published on EMBO Reports. Beijing Institute of Genomics, Chinese Academy of Sciences and Peking University first hospital cooperated and finished this result. In this research, they showed that AsA and AsA’s derivative—2-phosphate sesquimagnesium (APM) can significantly increase 5hmC’s level at physiological concentrations. Meanwhile, they can also inhibite the malignant phenotype of clear-cell renal cell carcinoma (ccRCC) cells in vitro and in vivo. The 5hmC levels were both increased in two ccRCC cell lines via long-term compounds’ culture at physiological concentration. Additionally, AsA re-established the 5hmC landscape in xenograft tumors and primary cells from ccRCC patients. From the results of hMeDIP-seq and ChIP-seq, both AsA compounds can specifically restore the 5hmC pattern of tumor cells, what’s made them more like normal tissue cells’ state; and these compounds also restored 5hmC peaks occur preferentially at enhancers, especially super-enhancers. All in all, it’s a strong proof of concept for epigenetic differentiation therapy with both AsA and its derivative APM at physiological concentrations by 5hmC reprogramming in ccRCC. Meanwhile, their results also showed that vitamin C treatment inhibited the growth of ccRCC cells at least partially by regulating TET activity. This study serves as important hypothesis-generating findings that may initiate new clinical trials for kidney cancer, especially using oxidation-resistant vitamin C derivatives. Schematic diagram of Vitamin C inhibits tumors (Image by CI Weimin's group) Contact： Prof. CI Weimin Email: ciwm@big.ac.cn CAS Key Laboratory of Genomic and Precision Medicine 
