Loss of 5-hydroxymethylcytosine is linked to gene body hypermethylation in kidney cancer

Abstract

Both 5-methylcytosine (5mC) and its oxidized form 5-hydroxymethylcytosine (5hmC) have been proposed to be involved in tumorigenesis. Because the readout of the broadly used 5mC mapping method, bisulfite sequencing (BS-seq), is the sum of 5mC and 5hmC levels, the 5mC/5hmC patterns and relationship of these two modifications remain poorly understood. By profiling real 5mC (BS-seq corrected by Tet-assisted BS-seq, TAB-seq) and 5hmC (TAB-seq) levels simultaneously at single-nucleotide resolution, we here demonstrate that there is no global loss of 5mC in kidney tumors compared with matched normal tissues. Conversely, 5hmC was globally lost in virtually all kidney tumor tissues. The 5hmC level in tumor tissues is an independent prognostic marker for kidney cancer, with lower levels of 5hmC associated with shorter overall survival. Furthermore, we demonstrated that loss of 5hmC is linked to hypermethylation in tumors compared with matched normal tissues, particularly in gene body regions. Strikingly, gene body hypermethylation was significantly associated with silencing of the tumor-related genes. Downregulation of IDH1 was identified as a mechanism underlying 5hmC loss in kidney cancer. Restoring 5hmC levels attenuated the invasion capacity of tumor cells and suppressed tumor growth in a xenograft model. Collectively, our results demonstrate that loss of 5hmC is both a prognostic marker and an oncogenic event in kidney cancer by remodeling the DNA methylation pattern.

Aberrant gene-specific DNA methylation signature analysis in cervical cancer

“…4 The distribution of 5-hmC is reported in many different tissues and cell types, and is abundant in embryonic stem cells and adult neuronal cells. 44 Although the biological function of 5-hmC is yet to be completely understood, many studies have reported the global loss of 5-hmC in cancer [45][46][47] and this may be related to reduced 5-mc levels. More recently, existence of 5-hmC inside mitochondria has also been reported.…”

The Influence of an Epigenetics Diet on the Cancer Epigenome

“…In an epigenome-wide study comparing regular kidney cells with clear cell renal cell carcinoma, it was actually determined that loss of 5hmC was linked to gene body hypermethylation upon TAB-seq analysis. Interestingly, there were no differences in the levels of 5mC [12].…”

Regulation and Functional Significance of 5-Hydroxymethylcytosine in Cancer

“…Invariably reduced levels of 5hmC have been reported in tumors of the lung, colon, brain, breast, liver, prostate, kidney, melanoma, etc, compared to its respective normal tissues [21][22][23]. This loss of 5hmC in genomic context may lead to gene body hypermethylation as observed in kidney cancer and can hypermethylate promoters of tumor suppressor genes (TSG) that are frequently observed in cancers [24]. Reduced 5hmC is a predictive marker for poor prognosis and survival for multiple cancers like breast, astrocytoma, laryngeal squamous cell carcinoma, renal, oesophageal, gastric and hepatocellular carcinoma (HCC) [24][25][26][27][28][29][30].…”

“…This loss of 5hmC in genomic context may lead to gene body hypermethylation as observed in kidney cancer and can hypermethylate promoters of tumor suppressor genes (TSG) that are frequently observed in cancers [24]. Reduced 5hmC is a predictive marker for poor prognosis and survival for multiple cancers like breast, astrocytoma, laryngeal squamous cell carcinoma, renal, oesophageal, gastric and hepatocellular carcinoma (HCC) [24][25][26][27][28][29][30]. Moreover, mutations in TET2 are frequently observed with decrease in 5hmC in hematological cancers, additionally mutations of 5hmC regulating enzymes like IDH1/2, SDH and FH were also observed [19,20,31,32].…”