Current and Potential Anticancer Drugs Targeting Members of the UHRF1 Complex Including Epigenetic Modifiers
Affiliation: Laboratory for Biomarker Development, The Institute of Physical and Chemical Research, Center for Genomic Medicine, RIKEN, Tokyo 108-8639, Japan.
Keywords: Epigenetics, histone modifications, DNA methylation, UHRF1, DNMT inhibitors, HDAC inhibitors, PLK1 inhibitors, PKA, PK2, G9a, PCNA, histone methyltransferases, DNMTs, ICBP90, CTCL, DNMT, Cisplatin, anorexia, neutropenia, thrombocytopenia, myelodyplastic syndromes, PLK1, cAMP, GEM, GWAS, Doxil, Abraxan, HDAC, hydroxywortmannin, HDM2, G9a/EHMT2, Tip60
Epigenetic modulators play significant roles in carcinogenesis. DNA methylation and histone modifications are the two major epigenetic modifications involved in transcriptional regulation. Many histone modification enzymes and DNMTs are up-regulated in cancer cells, and contribute to malignant transformation. The majority of the current “new generation” of anticancer drugs target abnormally overexpressed oncogenic proteins such as kinases or receptors which mediate oncogenic signal transmission. Overexpression or accumulation of these oncoproteins in cancer is caused directly or indirectly by genetic or epigenetic abnormalities in tumor-associated genes. Among these changes, epigenetic changes in DNA and histones can be caused by aberrant expression of epigenetic modulator proteins in cells. Recently, it has been revealed that UHRF1, which is up-regulated in various cancers, links DNA methylation and histone modifications through binding to hemi-methylated DNA, and also to trimethylated histone H3K9. The UHRF1 complex includes HDAC1, Tip60, G9a, and maintenance and de novo DNMTs. Many of these are reported to be involved in carcinogenesis. Several anticancer drugs targeting epigenetic-machinery such as HDAC inhibitors, and DNMT inhibitors have been developed. Even though these drugs showed some effect on several types of cancer, mild to severe adverse reactions have been observed. In this article, the relevant patents on the strategies to develop safer anticancer drugs targeting epigenetic modulators, focusing on members and modifiers of the UHRF1 complex, are discussed.
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