Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer

Abstract

CpG island hypermethylation and global genomic hypomethylation are common epigenetic features of cancer cells. Less attention has been focused on histone modifications in cancer cells. We characterized post-translational modifications to histone H4 in a comprehensive panel of normal tissues, cancer cell lines and primary tumors. Using immunodetection, high-performance capillary electrophoresis and mass spectrometry, we found that cancer cells had a loss of monoacetylated and trimethylated forms of histone H4. These changes appeared early and accumulated during the tumorigenic process, as we showed in a mouse model of multistage skin carcinogenesis. The losses occurred predominantly at the acetylated Lys16 and trimethylated Lys20 residues of histone H4 and were associated with the hypomethylation of DNA repetitive sequences, a well-known characteristic of cancer cells. Our data suggest that the global loss of monoacetylation and trimethylation of histone H4 is a common hallmark of human tumor cells.

Opposing effects of hMOF and SIRT1 on H4K16 acetylation and the sensitivity to the topoisomerase II inhibitor etoposide

“…SK-N-BE(2) is a highly malignant cell line derived from chemotherapy-resistant neuroblastoma, which presents an intrinsic resistance to multiple drugs including several DNA-damaging agents (Keshelava et al, 1998). Interestingly, all drug-resistant cancer cells analyzed exhibited a lower level of H4K16 acetylation compared with the drug-sensitive neural stem cells (Figure 3c) in part consistent with previous reports (Fraga et al, 2005). Treatment with TSA or VPA induced a clear increase in H4K16 acetylation in the cancer cells, whereas the primary neural stem cells showed high basal total H4K16 acetylation levels and this acetylation was in contrast unaffected by HDACi treatment.…”

“…Importantly, this single histone modification influences both higher-order chromatin structure and functional interactions between histones as well as a non-histone protein and the chromatin fiber (ShogrenKnaak et al, 2006). It has been shown that reduction in H4K16 acetylation correlate with tumor progression (Fraga et al, 2005). In addition, the enzymatic components of the regulatory system described in this study have been reported to be altered in cancer disease, although it should noted that both hMOF and SIRT1 have been associated with both survival and deathpromoting mechanisms.…”

“…The most pronounced increase in acetylation was detected at H4K16 as assessed by immunocytochemistry and immunoblotting (Figures 3a-c). H4K16 acetylation is known to influence histone-histone interactions and higher-order chromatin structure, and has previously been shown to display low levels of total acetylation in cancer cells (Fraga et al, 2005).…”

“…Many mechanisms have been proposed to explain the action of various HDACi, yet little is understood regarding how distinct HDACi can yield similar cellular effects seemingly regardless of structure and specificity. Interestingly, loss of total H4K16 acetylation has been suggested to represent one common hallmark of cancer cells (Fraga et al, 2005). The H4K16 residue is of particular interest as acetylation of this lysine residue is sufficient to induce reorganization of higher-order chromatin structure (Shogren-Knaak et al, 2006).…”

L’intrusion des régulateurs de l’épigénome mâle dans les cellules somatiques cancéreuses

“…Cette méthylation illégitime et la répression transcriptionnelle qui s'en suit, contribuent grandement à la transformation oncogénique des cellules [2]. Les données les plus récentes laissent penser que ces anomalies épigénétiques se produisant dans les cellules cancéreuses ne sont pas restreintes à la seule méthylation de l'ADN et englobent également les histones et leurs modifications post-traductionnelles [3]. Bien que l'on commence à caractériser de manière de plus en plus approfondie des perturbations épigéné-tiques observées dans les cellules cancéreuses, nous manquons de données sur l'origine de ces anomalies.…”