Strategies to re-express epigenetically silenced p15(INK4b) and p21(WAF1) genes in acute myeloid leukemia.
p15(INK4B) and p21(WAF1) are TGF-β targets that are silenced in leukemia by epigenetic mechanisms involving DNA methylation and/or histone modifications. Mechanisms for establishing and maintaining epigenetic silencing of p15(INK4B) and p21(WAF1) are not well established. The reversible nature of epigenetic modifications has lead to the development of drugs that target DNA methyltransferases, histone deacetylases, and histone methyltransferases, which have been used to re-express aberrantly silenced genes in leukemia. Recently, non-coding RNA, referred to as natural antisense transcripts (NATs), have been implicated in the regulation of epigenetic modifications. Here, we review epigenetic mechanisms for silencing p15(INK4B) and p21(WAF1) and the role of NATs in this process. We also review epigenetic drugs and drug combinations used to re-express p15(INK4B) and p21(WAF1). Lastly, we discuss the potential use of NATs to target the activity of epigenetic drugs to specific genes and to permanently re-express epigenetically silenced genes.
Department of Biochemistry and Cancer Stem Cell Research Group, University of Saskatchewan, Saskatoon, SK, Canada. ron.geyer@usask.ca
C Ronald
CR
Geyer
D000818:Animals; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000096:biosynthesis* / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D016372:RNA, Antisense / Q000096:biosynthesis / Q000235:genetics; D022661:RNA, Untranslated / Q000096:biosynthesis / Q000235:genetics
C493956:CDKN1A protein, human; C493966:CDKN2B protein, human; D050762:Cyclin-Dependent Kinase Inhibitor p15; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016372:RNA, Antisense; D022661:RNA, Untranslated