Epigenetics provides a new generation of oncogenes and tumour-suppressor genes

Abstract

Cancer is nowadays recognised as a genetic and epigenetic disease. Much effort has been devoted in the last 30 years to the elucidation of the 'classical' oncogenes and tumour-suppressor genes involved in malignant cell transformation. However, since the acceptance that major disruption of DNA methylation, histone modification and chromatin compartments are a common hallmark of human cancer, epigenetics has come to the fore in cancer research. One piece is still missing from the story: are the epigenetic genes themselves driving forces on the road to tumorigenesis? We are in the early stages of finding the answer, and the data are beginning to appear: knockout mice defective in DNA methyltransferases, methyl-CpG-binding proteins and histone methyltransferases strongly affect the risk of cancer onset; somatic mutations, homozygous deletions and methylation-associated silencing of histone acetyltransferases, histone methyltransferases and chromatin remodelling factors are being found in human tumours; and the first cancer-prone families arising from germline mutations in epigenetic genes, such as hSNF5/INI1, have been described. Even more importantly, all these 'new' oncogenes and tumour-suppressor genes provide novel molecular targets for designed therapies, and the first DNA-demethylating agents and inhibitors of histone deacetylases are reaching the bedside of patients with haematological malignancies.

Males absent on the first (MOF): from flies to humans

“…In addition to the classical mutations or translocations of oncogenes and tumor suppressors, we are finding changes in the epigenetic profile of most cancers (Esteller, 2006;Ting et al, 2006). These changes manifest as incorrect methylation of CpG islands of DNA, shifts in the covalent modification patterns of histones or as an impaired ability to remodel nucleosomes (Esteller, 2006;Ting et al, 2006). Since most of these epigenetic changes are reversible they represent an attractive target for the treatment of cancer.…”

Global and gene‐specific promoter methylation changes are related to anti‐B[a]PDE‐DNA adduct levels and influence micronuclei levels in polycyclic aromatic hydrocarbon‐exposed individuals

“…However, an investigative approach exclusively based on genetic damage, as well as on inheritance of genetic variants, has been revealed to be insufficient to account for multistage carcinogenic processes. 2 It has been proposed that DNA methylation, one of the best known epigenetic mechanisms, shares critical roles with DNA mutations in the theoretical continuum for exposure to cancer. 3,4 One potential mechanism for environmental factors is through hypermethylation or hypomethylation on somatic cells, leading to activation or silencing of key genes in critical pathways of cancer.…”

De la régulation du génome à la progression tumorale

“…En effet, l'enroulement de l'ADN autour d'un octamère de protéines histones pour former le nucléosome constitue une barrière naturelle pour les machineries nucléaires nécessitant d'avoir accès au matériel génétique. En conséquence, l'altération de la structure nucléosomique ou de l'agencement des nucléosomes le long de la double hélice, en affectant le degré d'accessibilité de l'ADN, régule de nombreux processus biologiques et pathologiques de la cellule [1,2]. Parmi les différentes voies de régulation qui ont été caractérisées et agissent souvent de manière coordonnée, la plus étudiée reste le processus de modification post-traductionnelle des queues amino-terminales des histones.…”

“…Comme elle intervient de manière déterminante dans de nombreux processus biologiques, l'altération de l'activité des HAT et HDAC est associée au dérèglement d'un nombre plus ou moins important de gènes ou de facteurs nucléaires pouvant jouer un rôle dans le processus de transformation et de cancérogenèse [2,28]. Toutefois la preuve de l'implication directe de l'acéty-lation des histones dans ces processus n'a été acquise que récemment.…”