• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • Histone modification especially histone lysine methylation


    Histone modification, especially histone 3-lysine-9 methylation (H3K9) is a common mechanism of transcriptional repression of gene expression (Yoruker et al., 2012). SETDB1, which belongs to the family of SET domain histone methyltransferases including Suv39H, EZH2 and G9a, contains a highly conserved motif of 150-amino acids and is involved in the modulations of BI6727 Supplier structure (Yang et al., 2002). The SETDB1 protein structure contains a CpG DNA methyl-binding domain, which regulates H3K9 methylation activity (Ceol et al., 2011). The CpG island methylation of the CDKN2A gene promoter and expression of SETDB1 in sporadic cutaneous melanomas are highly correlated with histologic prognostic parameters (Kostaki et al., 2014). Methylation of the CDKN2A promoter is associated with 52% (12/23) of NRAS-mutated cutaneous melanomas compared with BRAF-mutated (7%, 2/27) tumors (Jonsson et al., 2010). EZH2, a histone methyltransferase and a catalytic subunit of the PRC2 polycomb repressor, mediates gene silencing by tri-methylating H3K27 of various target gene promoters (Bracken et al., 2007; Cao et al., 2002). SNF5, one of the core subunits of Brahma-associated factor (BAF) chromatin remodeler complexes, down-regulates EZH2 transcription (Wilson et al., 2010). Thus, the loss of SNF5 function leads to increased EZH2 expression, thereby repressing the expression of CDKN2A through the tri-methylation of H3K27 in the CDKN2A promoter region (Wilson et al., 2010).
    Conclusion A high frequency of genetic and epigenetic alterations (e.g., promoter hyper-methylation, homozygous deletion or mutation) in the CDKN2A gene has been observed in human cancer cell lines derived from various tumor types. However, a significantly lower frequency of CDKN2A abnormalities has been reported in fresh, non-cultured primary tumors and cell lines. Therefore, regulation of CDKN2A abnormalities will have benefits for the cancer prevention and/or therapy.
    Outstanding questions Besides genetic and epigenetic aberrations, the regulation of gene expression is also associated with the status of many other proteins, such as p53, BRAF, ataxia talengectia mutated (ATM), phosphatase and tensin homolog deleted at chromosome 10 (PTEN), KRAS and phosphatidylinositol 3-kinase (PI3-K) as well as the components of the CDKN2A promoter, such as the PRC1 and PRC2 complexes and long noncoding RNAs. HPV, a small DNA virus (major types HPV-16 and HPV-18) expresses E6 and E7 oncoproteins and is linked causally to most cervical cancers that show a high expression of p16INK4a (Kobalka et al., 2015; Munger et al., 2013; Pauck et al., 2014; Nehls et al., 2008). The E6 and E7 oncoproteins directly block p53 and pRb tumor suppressors resulting in the accumulation of p16INK4a, which is upstream of p53 and pRb (Dyson et al., 1989; Scheffner et al., 1993). HPV-infection-associated cervical cancer also mediates the high expression of p16INK4a by epigenetic modulation of the CDKN2A upstream promoter (Nehls et al., 2008; McLaughlin-Drubin et al., 2013). Thus in HPV-infection-associated cancer, we should consider the p16INK4a as a biomarker in an opposite manner than what is generally expected. Although smoking and/or drinking is a risk factor for lung, head and neck, and pancreatic cancers (Gillison et al., 2012; Jiao et al., 2007; Tam et al., 2013), meaningful correlations of p16INK4a expression with smoking or drinking are not yet supported by strong evidence (Jiao et al., 2007; Gillison et al., 2012; Tam et al., 2013). Because p16INK4a is a critical regulator of cell proliferation and is inactivated during the course of tumorigenesis, methods for restoration of p16INK4a function could provide good therapeutic strategies. To achieve this goal, the focus has been directed toward understanding the molecular mechanisms, especially genetic and epigenetic changes that lead to p16INK4a inactivation in cancer, and developing small molecule modifiers of these mechanistic switches. For example, ZBP-89 can induce the expression of p16INK4a (Zhang et al., 2010). Likewise, FOXA1 and jmjd3 enhance CDKN2A expression by direct transcriptional activation and promoter di-methylation, respectively. Thus, discovery of small molecule activators of ZBP-89, jmjd3 or FOXA1 might be a future research goal for developing novel anticancer therapies. On the other hand, factors that repress CDKN2A gene expression, such as SETDB1, EZH2, or PcB proteins, could be potential therapeutic targets to induce p16INK4a functionality and tumor suppression. Although several natural and synthetic compounds, such as genistein, sulforaphane, EGCG and 5-aza-CdR have been shown to intervene against the epigenetic silencing of CDKN2A, mechanism-based development of p16INK4a activators warrants further studies.