Methylation and Demethylation of Ink4 Locus in Cancer Development

The Ink4 locus at chromosome 9p21 encodes P15Ink4b, P14Arf, P16Ink4a, MTAP, ncRNA ANRIL/p15AS and p16AS, which play an important role in regulation of stem cell self-renewal. Loss of functions of these genes promotes cell proliferation through bypassing checkpoint between the G1 and S phase of the cell cycle. Transcriptional silence by methylation of CpG island around transcription starting site (TSS) is a frequent event in the early stage of carcinogenesis. Chronic inflammation is a strong initiator for methylation of CpG island of the Ink4a gene. Combination of transcriptional silencers such as Polycomb group (PcG) proteins with gene-specific ncRNA could result in histone modifications including trimethylation at H3K27 firstly, and then at H3K9 epigenetically. In the case of long-term silence of transcription, methylation of CpG sites initiates and spreads progressively within the full CpG islands of the target gene. The methylation status of Ink4a CpG island is very stable even if its host cells are fused with Ink4a active cells.