Euchromatic histone methyltransferase 2 inhibitor, BIX-01294, sensitizes human promyelocytic leukemia HL-60 and NB4 cells to growth inhibition and differentiation.
The involvement of histone lysine methyltransferases (HMT) in carcinogenesis is not well understood. Here, we describe a dose-dependent growth and survival inhibitory effects of BIX-01294, a specific inhibitor of euchromatic HMT2, in promyelocytic leukemia HL-60 and NB4 cells. BIX-01294 combined with all-trans retinoic acid or together with histone deacetylase and DNA methyltransferase inhibitors enhanced cell differentiation to granulocytes and induced cell line-specific changes in the expression of cell cycle-, survival- and differentiation regulating genes and proteins in association with histone modification state. Our results suggest that targeting EHMT2 may be of therapeutical benefits in myeloid leukemia.
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT 08662 Vilnius, Lithuania.
Jurate
J
Savickiene
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT 08662 Vilnius, Lithuania.
Grazina
G
Treigyte
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT 08662 Vilnius, Lithuania.
Ieva
I
Stirblyte
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT 08662 Vilnius, Lithuania.
Giedre
G
Valiuliene
Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT 08662 Vilnius, Lithuania. Electronic address: ruta.navakauskiene@bchi.vu.lt.
Ruta
R
Navakauskiene
D001381:Azepines / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006649:Histocompatibility Antigens; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000473:pathology; D011799:Quinazolines / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology
D001381:Azepines; C518299:BIX 01294; D006649:Histocompatibility Antigens; D011799:Quinazolines; D014212:Tretinoin; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase
Acute myeloid leukemia; BIX-01294; Cell-cycle arrest; Differentiation; Histone modifications