Histone deacetylase inhibitors promote the tumoricidal effect of HAMLET.
Histone deacetylase inhibitors (HDIs) and HAMLET (human alpha-lactalbumin made lethal to tumor cells) interact with histones, modify the structure of chromatin, and trigger tumor cell death. This study investigated how the combination of HDIs and HAMLET influences cell viability, histone acetylation, and DNA integrity. The pretreatment of tumor cells with HDIs was shown to enhance the lethal effect of HAMLET and the histone hyperacetylation response to HDIs increased even further after HAMLET treatment. HDIs and HAMLET were shown to target different histone domains as HAMLET bound tailless core histones, whereas HDIs modify the acetylation of the histone tail. DNA damage in response to HAMLET was increased by HDIs. The DNA repair response (p21WAFI expression) was induced by both agonists but abolished when the two agonists were combined. The results suggest that the synergy of HDIs and HAMLET is based on different but converging death pathways, both involving chromatin alterations. We speculate that HAMLET and HDIs might be combined to promote tumor cell death in vivo.
Institute of Laboratory Medicine, Section of Microbiology, Immunology, and Glycobiology, Lund University, Lund, Sweden.
Patrick
P
Brest
Mattias
M
Gustafsson
Ann-Kristin
AK
Mossberg
Lotta
L
Gustafsson
Caroline
C
Duringer
Ali
A
Hamiche
Catharina
C
Svanborg
D000107:Acetylation / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols; D002470:Cell Survival / Q000187:drug effects*; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D006367:HeLa Cells / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D019169:Jurkat Cells / Q000187:drug effects; D007768:Lactalbumin / Q000494:pharmacology*; D009829:Oleic Acids / Q000494:pharmacology*; D000077337:Vorinostat
C493956:CDKN1A protein, human; D002843:Chromatin; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; C506422:HAMLET complex, human; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D009829:Oleic Acids; C012589:trichostatin A; D000077337:Vorinostat; D007768:Lactalbumin; D006655:Histone Deacetylases