Histone deacetylase inhibition overcomes drug resistance through a miRNA-dependent mechanism.
The treatment of specific tumor cell lines with poly- and oligoamine analogs results in a superinduction of polyamine catabolism that is associated with cytotoxicity; however, other tumor cells show resistance to analog treatment. Recent data indicate that some of these analogs also have direct epigenetic effects. We, therefore, sought to determine the effects of combining specific analogs with an epigenetic targeting agent in phenotypically resistant human lung cancer cell lines. We show that the histone deacetylase inhibitor MS-275, when combined with (N(1), N(11))-bisethylnorspermine (BENSpm) or (N(1), N(12))-bis(ethyl)-cis-6,7-dehydrospermine tetrahydrochloride (PG-11047), synergistically induces the polyamine catabolic enzyme spermidine/spermine N(1)-acetyltransferase (SSAT), a major determinant of sensitivity to the antitumor analogs. Evidence indicates that the mechanism of this synergy includes reactivation of miR-200a, which targets and destabilizes kelch-like ECH-associated protein 1 (KEAP1) mRNA, resulting in the translocation and binding of nuclear factor (erythroid-derived 2)-like 2 (NRF2) to the polyamine-responsive element of the SSAT promoter. This transcriptional stimulation, combined with positive regulation of SSAT mRNA and protein by the analogs, results in decreased intracellular concentrations of natural polyamines and growth inhibition. The finding that an epigenetic targeting agent is capable of inducing a rate-limiting step in polyamine catabolism to overcome resistance to the antitumor analogs represents a completely novel chemotherapeutic approach. In addition, this is the first demonstration of miRNA-mediated regulation of the polyamine catabolic pathway. Furthermore, the individual agents used in this study have been investigated clinically; therefore, translation of these combinations into the clinical setting holds promise.
Corresponding Author: Robert A. Casero, Jr., CRB 1 Room 551, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans Street, Bunting Blaustein Building, Baltimore, MD 21287. rcasero@jhmi.edu.
Tracy
T
Murray-Stewart
Christin L
CL
Hanigan
Patrick M
PM
Woster
Laurence J
LJ
Marton
Robert A
RA
Casero
D000123:Acetyltransferases / Q000096:biosynthesis; D001549:Benzamides / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D008660:Metabolism / Q000187:drug effects / Q000235:genetics; D035683:MicroRNAs / Q000235:genetics*; D011073:Polyamines / Q000008:administration & dosage* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage*; D013096:Spermine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D001549:Benzamides; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D035683:MicroRNAs; D011073:Polyamines; D011725:Pyridines; D013096:Spermine; D000099228:Diamine N-Acetyltransferase; C415967:(N(1),N(12))bis(ethyl)-6,7-dehydrospermine; C431364:KEAP1 protein, human; C533896:MIRN200 microRNA, human; C118739:entinostat