Blood Journal
Leading the way in experimental and clinical research in hematology

KLF9 is a novel transcriptional regulator of bortezomib- and LBH589-induced apoptosis in multiple myeloma cells

  1. Sudha Mannava1,
  2. DaZhong Zhuang1,
  3. Jayakumar R Nair2,
  4. Rajat Bansal3,
  5. Joseph A. Wawrzyniak1,
  6. Shoshanna N. Zucker1,
  7. Emily E. Fink1,
  8. Kalyana C. Moparthy1,
  9. Qiang Hu4,
  10. Song Liu4,
  11. Lawrence H. Boise5,
  12. Kelvin P. Lee2, and
  13. Mikhail A. Nikiforov1,*
  1. 1 Department of Cell Stress Biology, Roswell Park Cancer Institute, Buffalo, NY, United States;
  2. 2 Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY, United States;
  3. 3 Department of Cell Stress Biology, Roswell Park Cancer Institute, Bufflao, NY, United States;
  4. 4 Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, United States;
  5. 5 Department of Hematology and Medical Oncology, Emory University School of Medicine and the Winship Cancer Institute, Atlanta, GA, United States
  1. * Corresponding author; email: mikhail.nikiforov{at}roswellpark.org

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 that responded to bortezomib compared to non-responders. 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 pro-apoptotic gene NOXA. Importantly, KLF9 knock-down impaired NOXA up-regulation and apoptosis caused by bortezomib, LBH589 or 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.

  • Submitted April 5, 2011.
  • Accepted November 25, 2011.