HERV-K and LINE-1 DNA Methylation and Reexpression in Urothelial Carcinoma

Abstract

Changes in DNA methylation frequently accompany cancer development. One prominent change is an apparently genome-wide decrease in methylcytosine that is often ascribed to DNA hypomethylation at retroelements comprising nearly half the genome. DNA hypomethylation may allow reactivation of retroelements, enabling retrotransposition, and causing gene expression disturbances favoring tumor development. However, neither the extent of hypomethylation nor of retroelement reactivation are precisely known. We therefore assessed DNA methylation and expression of three major classes of retroelements (LINE-1, HERV-K, and AluY) in human urinary bladder cancer tissues and cell lines by pyrosequencing and quantitative reverse transcription–polymerase chain reaction, respectively. We found substantial global LINE-1 DNA hypomethylation in bladder cancer going along with a shift toward full-length LINE-1 expression. Thus, pronounced differences in LINE-1 expression were observed, which may be promoted, among others, by LINE-1 hypomethylation. Significant DNA hypomethylation was found at the HERV-K_22q11.23 proviral long terminal repeat (LTR) in bladder cancer tissues but without reactivation of its expression. DNA methylation of HERVK17, essentially absent from normal urothelial cells, was elevated in cell lines from invasive bladder cancers. Accordingly, the faint expression of HERVK17 in normal urothelial cells disappeared in such cancer cell lines. Of 16 additional HERV-Ks, expression of 7 could be detected in the bladder, albeit generally at low levels. Unlike in prostate cancers, none of these showed significant expression changes in bladder cancer. In contrast, expression of the AluYb8 but not of the AluYa5 family was significantly increased in bladder cancer tissues. Collectively, our findings demonstrate a remarkable specificity of changes in expression and DNA methylation of retroelements in bladder cancer with a significantly different pattern from that in prostate cancer.

LINE-1 Hypomethylation in Blood and Tissue Samples as an Epigenetic Marker for Cancer Risk: A Systematic Review and Meta-Analysis

“…The most frequent tumor type in study was colorectal cancer analyzed in eight studies [15] , [21] , [28] – [33] , followed by seven studies that evaluated methylation level in gastric cancer [23] , [27] , [32] , [34] – [37] , five in hepatocellular carcinoma [25] , [38] – [41] , four in bladder cancer [1] , [14] , [42] , [43] and head and neck carcinoma [10] , [44] – [46] , two in lung cancer [47] , [48] and breast cancer [24] , [49] , and single studies assessed methylation levels in renal cell cancer [50] , prostate cancer [51] , neuroendocrine tumor [52] , ovarian cancer [53] , thyroid cancer [54] , esophageal cancer [26] , cervix cancer [55] , endometrial cancer [32] , skin melanoma [22] , testicular cancer [56] , leukemia [57] , multiple myeloma [58] , paraganglioma [59] , fibrolamellar carcinoma [60] and gastrointestinal [61] . Four studies evaluated methylation level in several cancer sites [13] , [28] , [29] , [32] .…”

LINE‐1 hypomethylation induced by reactive oxygen species is mediated via depletion of S‐adenosylmethionine

“…Hypomethylation of LINE-1 is associated with an increased risk for bladder cancer development. 9,22 We recently found that LINE-1 hypomethylation is associated with increased oxidative stress in both bladder cancer patients and healthy controls. 9 Moreover, we demonstrated that ROS was an inducing factor for LINE-1 hypomethylation in the bladder cancer cell line.…”

Basic Hallmarks of Urothelial Cancer Unleashed in Primary Uroepithelium by Interference with the Epigenetic Master Regulator ODC1

“…Global DNA hypomethylation, a genome-wide decrease in methylcytosine, occurs concomitantly, affecting in particular endogenous retroviruses (HERVs) and retrotransposons (SINEs and LINEs) and may result in their transcriptional reactivation 12 . In particular, substantial global LINE-1 DNA hypomethylation in bladder cancer is accompanied by a shift toward expression of full-length LINE-1 elements 13 .…”