Document Detail


KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells.
MedLine Citation:
PMID:  22144178     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Sudha Mannava; DaZhong Zhuang; Jayakumar R Nair; Rajat Bansal; Joseph A Wawrzyniak; Shoshanna N Zucker; Emily E Fink; Kalyana C Moparthy; Qiang Hu; Song Liu; Lawrence H Boise; Kelvin P Lee; Mikhail A Nikiforov
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2011-12-05
Journal Detail:
Title:  Blood     Volume:  119     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-10     Completed Date:  2012-04-03     Revised Date:  2013-10-22    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1450-8     Citation Subset:  AIM; IM    
Affiliation:
Department of Cell Stress Biology,Roswell Park Cancer Institute, Elm & Carlton Sts., Buffalo, NY 14263, USA.
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents / pharmacology
Apoptosis / drug effects*
Blotting, Western
Boronic Acids / pharmacology*
Cell Line, Tumor
Cell Survival / drug effects
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
Humans
Hydroxamic Acids / pharmacology*
Indoles
Kruppel-Like Transcription Factors / genetics*,  metabolism
Multiple Myeloma / genetics*,  metabolism,  pathology
Oligonucleotide Array Sequence Analysis
Promoter Regions, Genetic / genetics
Protein Binding
Proto-Oncogene Proteins c-bcl-2 / genetics,  metabolism
Pyrazines / pharmacology*
RNA Interference
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
R01 CA120244/CA/NCI NIH HHS; R01 CA120244/CA/NCI NIH HHS; R01 CA121044/CA/NCI NIH HHS; R01 CA127910/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Boronic Acids; 0/Hydroxamic Acids; 0/Indoles; 0/KLF9 protein, human; 0/Kruppel-Like Transcription Factors; 0/PMAIP1 protein, human; 0/Proto-Oncogene Proteins c-bcl-2; 0/Pyrazines; 0/Transcription Factors; 0/bortezomib; 0/panobinostat
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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