Genetic and epigenetic modeling of the origins of multidrug-resistant cells in a human sarcoma cell line.
The origin of drug-resistant cells in human cancers has been a fundamental problem of cancer pharmacology. Two major contrasting hypotheses (genetics versus epigenetics) have been proposed to elucidate the mechanisms of acquired drug resistance. In this study, we answer these fundamental questions through investigation of the genetic and epigenetic pathways that control the origin of ABCB1 (MDR1) gene activation with acquired multidrug resistance in drug-sensitive human sarcoma (MES-SA cells). The genetic and epigenetic bases of this selected activation involve the initiation of transcription at a site 112 kb upstream of the ABCB1 proximal promoter (P1) in the drug-resistant cells. This activation was associated with a chromatin-remodeling process characterized by an increase in acetylated histone H3 within a 968-bp region 5' of the ABCB1 upstream promoter. These alterations provide both genetic and epigenetic susceptibility for ABCB1 expression in drug-resistant cells. Complete activation of the ABCB1 gene through the coding region was proposed by interactions of selected trans-alterations or epigenetic changes on the ABCB1 proximal promoter, which occurred during initial drug exposure. Thus, our data provide evidence for a major genomic alteration that changes the chromatin structure of the ABCB1 upstream promoter via acetylation of histone H3 initiating ABCB1 activation, further elucidating the genetic and epigenetic bases that determine chemotherapeutic response in drug-resistant derivatives of MES-SA cells.
Chen
Kevin G
KG
Division of Oncology, Department of Medicine and Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA, USA. cheng@mail.nih.gov
Wang
Yan C
YC
Schaner
Marci E
ME
Francisco
Brian
B
Durán
George E
GE
Juric
Dejan
D
Huff
Lyn M
LM
Padilla-Nash
Hesed
H
Ried
Thomas
T
Fojo
Tito
T
Sikic
Branimir I
BI
D000107:Acetylation; D001483:Base Sequence; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D005260:Female; D005786:Gene Expression Regulation; D019450:Genes, MDR / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012509:Sarcoma / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D014594:Uterine Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism
D002352:Carrier Proteins; D002843:Chromatin; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; C477805:RUNDC3B protein, human; D004317:Doxorubicin