Chemoresistance to depsipeptide FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is mediated by reversible MDR1 induction in human cancer cell lines.
Histone acetylation status, an epigenetic determinant of gene transcription, is controlled by histone acetyltransferases (HATs) and histone deacetylases (HDACs). The potent HDAC inhibitor FK228 [(E)-(1S,4S,10S,21R)-7-[(Z)-ethylidene]-4,21-diisopropyl-2-oxa-12,13-dithia-5,8,20,23-tetraazabicyclo[8,7,6]-tricos-16-ene-3,6,9,22-pentanone] is a substrate for multidrug resistance protein (MDR1) and multidrug resistance-associated protein 1 (MRP1), both of which mediate FK228 resistance. To determine the mechanisms underlying acquired FK228 resistance, we developed four FK228-resistant cell lines from HCT-15, IGROV1, MCF7, and K562 cells by stepwise increases in FK228 exposure. Parent and resistant cells were characterized using a 70-oligomer cDNA microarray, real-time reverse transcription-polymerase chain reaction (RT-PCR), Western blot, and cytotoxicity assays. At both mRNA and protein levels, MDR1, but not MRP1 or other potential resistance genes, was strongly up-regulated in all resistant cell lines. HAT or HDAC activities were unaffected in resistant cells, consistent with a lack of cross-resistance to HDAC inhibitors that are not MDR1 substrates. FK228 was found to reversibly induce MDR1 expression by HDAC inhibition and subsequent histone hyperacetylation at the MDR1 promoter, as shown by real-time RT-PCR, Western blot, and chromatin immunoprecipitation. This study reveals a significant role of histone acetylation in MDR1 transcription, which seems to mediate FK228 resistance.
Xiao
Jim J
JJ
College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Huang
Ying
Y
Dai
Zunyan
Z
Sadée
Wolfgang
W
Chen
Jiyun
J
Liu
Shujun
S
Marcucci
Guido
G
Byrd
John
J
Covey
Joseph M
JM
Wright
John
J
Grever
Michael
M
Chan
Kenneth K
KK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000123:Acetyltransferases / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D047630:Depsipeptides / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D047468:Immunoprecipitation; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D002843:Chromatin; D018076:DNA, Complementary; D047630:Depsipeptides; C087123:romidepsin; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D006655:Histone Deacetylases