5-hydroxymethylcytosine (5hmC) is considered as a prevalent DNA modification and plays an important role in regulating gene expression and tissue specificity. Loss of 5hmC has been reported in multiple cancers.

Solid tumors are composed of cancer cells and cancer stem cells which alter cancer cellular phenotypes to increase cancer cell plasticity. The shift between different phenotypic states of cancer cells is controlled via both genetic and epigenetic alterations. Although DNA 5hmC serves as a good biomarker for cancer diagnosis and prognosis, there is little research aimed at the functional roles of 5hmC in cancers. Moreover, whether and how 5hmC differentially regulates the differentiated tumor cells and cancer stem cells remain elusive.

Recently, researchers from the Beijing Institute of Genomics of the Chinese Academy of Sciences (China National Center for Bioinformation) reported the epigenomic features and profiles of 5hmC in genitourinary cancers, and identified that regional gain and global loss of 5-hydroxymethylcytosine coexist in genitourinary cancers and regulate different oncogenic pathways. This study, published online in Clinical Epigenetics, provides a molecular link between cancer stem cell biology and aggressive epithelial cancers in genitourinary cancers.

By systemically investigating the genome-wide patterns and functional relevance of 5hmC in genitourinary cancers across integrating 5hmC and transcriptome data, the researchers demonstrated that regional gain of 5hmC also exists in genitourinary cancers involved in stemness related pathways, in addition to global loss of 5hmC. They confirmed that gain of 5hmC occurred in cancer stem cell-like cells induced by 3D soft fibrin gel in prostate cancer cell lines.

Then, researchers developed a malignant signature associated with cancer progression to an aggressive phenotype by integrative analysis of genome-wide 5hmC alterations and differential gene expression in human prostate cancer cell lines. Interestingly, they observed the reprogramming drug named ascorbyl phosphate magnesium (APM) which restored DNA hydroxymethylation and killed the cancer stem-like cells in prostate cancer cell lines via regulated different pathways such as apoptosis.

Taken together, this study demonstrates a novel role of 5hmC in regulation of cancer stem-like cells, and a potential intervention strategy for targeting genitourinary cancer stem cells with vitamin C and its derivatives.