title: KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells.
abstract: Bortezomib, a therapeutic agent for multiple myeloma (MM) and mantle cell lymphoma, suppresses proteosomal degradation leading to substantial changes in cellular transcriptional programs and ultimately resulting in apoptosis. Transcriptional regulators required for bortezomib-induced apoptosis in MM cells are largely unknown. Using gene expression profiling, we identified 36 transcription factors that displayed altered expression in MM cells treated with bortezomib. Analysis of a publically available database identified Kruppel-like family factor 9 (KLF9) as the only transcription factor with significantly higher basal expression in MM cells from patients who responded to bortezomib compared with nonresponders. We demonstrated that KLF9 in cultured MM cells was up-regulated by bortezomib; however, it was not through the induction of endoplasmic reticulum stress. Instead, KLF9 levels correlated with bortezomib-dependent inhibition of histone deacetylases (HDAC) and were increased by the HDAC inhibitor LBH589 (panobinostat). Furthermore, bortezomib induced binding of endogenous KLF9 to the promoter of the proapoptotic gene NOXA. Importantly, KLF9 knockdown impaired NOXA up-regulation and apoptosis caused by bortezomib, LBH589, or a combination of theses drugs, whereas KLF9 overexpression induced apoptosis that was partially NOXA-dependent. Our data identify KLF9 as a novel and potentially clinically relevant transcriptional regulator of drug-induced apoptosis in MM cells.
authors.affiliation: Department of Cell Stress Biology,Roswell Park Cancer Institute, Elm & Carlton Sts., Buffalo, NY 14263, USA.
authors.forename: Sudha
authors.initials: S
authors.lastname: Mannava
authors.forename: DaZhong
authors.initials: D
authors.lastname: Zhuang
authors.forename: Jayakumar R
authors.initials: JR
authors.lastname: Nair
authors.forename: Rajat
authors.initials: R
authors.lastname: Bansal
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Wawrzyniak
authors.forename: Shoshanna N
authors.initials: SN
authors.lastname: Zucker
authors.forename: Emily E
authors.initials: EE
authors.lastname: Fink
authors.forename: Kalyana C
authors.initials: KC
authors.lastname: Moparthy
authors.forename: Qiang
authors.initials: Q
authors.lastname: Hu
authors.forename: Song
authors.initials: S
authors.lastname: Liu
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Boise
authors.forename: Kelvin P
authors.initials: KP
authors.lastname: Lee
authors.forename: Mikhail A
authors.initials: MA
authors.lastname: Nikiforov
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D000077767:Panobinostat; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D006877:Hydroxamic Acids; D007211:Indoles; C489676:KLF9 protein, human; D051741:Kruppel-Like Transcription Factors; C498702:PMAIP1 protein, human; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D014157:Transcription Factors; D000069286:Bortezomib; D000077767:Panobinostat