Drug discovery targeting epigenetic codes: the great potential of UHRF1, which links DNA methylation and histone modifications, as a drug target in cancers and toxoplasmosis.
UHRF1 plays a central role in transferring methylation status from mother cells to daughter cells. Its SRA domain recognizes hemi-methylated DNA that appears in daughter DNA strands during duplication of DNA. UHRF1 recruits DNMT1 to the site and methylates both strands. UHRF1 also binds to HDAC1 and di- and tri-methyl K9 histone H3, ubiquitinates histone H3, and associates with heterochromatin formation, indicating that UHRF1 links histone modifications, DNA methylation, and chromatin structure. UHRF1 is a direct target of E2F1 and promotes G1/S transition. The tumor suppressor p53, which is deficient in 50% of cancers, down-regulates UHRF1 through up-regulation of p21/WAF1 and subsequent deactivation of E2F1. The expression levels of UHRF1 are up-regulated in many cancers, probably partially because of the absence of wild type p53, but it is probably regulated by several other factors. Knockdown of UHRF1 expression in cancer cells suppressed cell growth, suggesting that UHRF1 can be a useful anticancer drug target. Recently, it was revealed that UHRF1 plays important roles not only in carcinogenesis, but also in toxoplasmosis, which is occasionally fatal to people with a weakened immune system, and can cause blindness in the major pathology of ocular toxoplasmosis. Toxoplasma gondii, which causes toxoplasmosis, utilizes UHRF1 to control the cell cycle phase and enhance its proliferation. Thus, knockdown of UHRF1 can be effective at stopping the proliferation of the parasites in infected cells. In this review, we discuss several possible methods that can inhibit the multiple unique functions of UHRF1, which can be utilized for treating cancers and toxoplasmosis.
Unoki
Motoko
M
Laboratory for Biomarker Development, The Institute of Physical and Chemical Research, Center for Genomic Medicine, RIKEN, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. unokim@ims.u-tokyo.ac.jp
Brunet
Julie
J
Mousli
Marc
M
D022762:CCAAT-Enhancer-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D019496:Cancer Vaccines / Q000494:pharmacology / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000096:biosynthesis; D019175:DNA Methylation / Q000187:drug effects*; D015195:Drug Design; D044127:Epigenesis, Genetic / Q000187:drug effects*; D006570:Heterochromatin / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006790:Host-Parasite Interactions / Q000187:drug effects; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology / Q000627:therapeutic use; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use; D014123:Toxoplasmosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D044767:Ubiquitin-Protein Ligases
D022762:CCAAT-Enhancer-Binding Proteins; D019496:Cancer Vaccines; D016207:Cytokines; D006570:Heterochromatin; D006657:Histones; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; C406364:UHRF1 protein, human; D044767:Ubiquitin-Protein Ligases