miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth

Blood Cancer J. 2016 Jan 15;6(1):e380. doi: 10.1038/bcj.2015.106.

Abstract

Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3'UTR and significantly reduced Sp1-driven nuclear factor-κB activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Base Sequence
  • Binding Sites
  • Caspase 3 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival / genetics
  • DNA Methylation
  • Disease Models, Animal
  • Down-Regulation
  • Gene Expression
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Gene Regulatory Networks*
  • Gene Silencing
  • Genes, Reporter
  • Humans
  • MicroRNAs / chemistry
  • MicroRNAs / genetics*
  • Multiple Myeloma / genetics*
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins c-myc / chemistry
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • RNA Interference
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • Sp1 Transcription Factor / chemistry
  • Sp1 Transcription Factor / genetics*
  • Sp1 Transcription Factor / metabolism

Substances

  • MIRN23a microRNA, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • RNA, Messenger
  • Sp1 Transcription Factor
  • Caspase 3