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5-Methylcytosine hydroxylation-mediated LINE-1 hypomethylation: a novel mechanism of proto-oncogenes activation in colorectal cancer?
  1. Abbes Belkhiri1,
  2. Wael El-Rifai1,2
  1. 1 Department of Surgery and Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  2. 2 Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, Tennessee, USA
  1. Correspondence to Professor Wael El-Rifai and Dr Abbes Belkhiri, Department of Surgery and Department of Cancer Biology, Vanderbilt University Medical Center, 760 Preston Research Building, 2220 Pierce Ave, Nashville, TN 37232-6308, USA; wael.el-rifai{at}vanderbilt.edu or abbes.belkhiri{at}vanderbilt.edu

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Commentary

The human genome comprises the most predominant long interspersed nuclear element-1 (LINE-1) sequences, which are non-long-terminal repeat retrotransposons. The majority of LINE-1 repeats are inactivated through truncation, inversion and mutation.1 Importantly, DNA methylation attenuates the transcriptional activation, amplification and recombination of LINE-1 sequences, thereby maintaining genome stability.2 Indeed, global DNA hypomethylation has been associated with increased genomic instability and tumourigenesis, suggesting a more important role for hypomethylation in human cancers than the hypermethylation-induced downregulation of some tumour suppressor genes.35 LINE-1 hypomethylation has been shown to associate with the clinicogenetic features of multiple myeloma6 and chronic myeloid leukaemia,7 poor prognosis in non-small cell lung cancer,8 and with more aggressive progression of colorectal cancer (CRC).9

The full-length LINE-1 sequence (6 Kb) includes a sense promoter regulating transcription of two open reading frames and an antisense promoter (ASP) in the 5′-untranslated region, which contains a CpG island—usually hypermethylated in normal cells—regulating transcription of adjacent genes in the opposite direction.1012 The ASP has been reported to function as an alternative transcription …

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