The PKC/NF-κB signaling pathway induces APOBEC3B expression in multiple human cancers

Cancer Res. 2015 Nov 1;75(21):4538-47. doi: 10.1158/0008-5472.CAN-15-2171-T. Epub 2015 Sep 29.

Abstract

Overexpression of the antiviral DNA cytosine deaminase APOBEC3B has been linked to somatic mutagenesis in many cancers. Human papillomavirus infection accounts for APOBEC3B upregulation in cervical and head/neck cancers, but the mechanisms underlying nonviral malignancies are unclear. In this study, we investigated the signal transduction pathways responsible for APOBEC3B upregulation. Activation of protein kinase C (PKC) by the diacylglycerol mimic phorbol-myristic acid resulted in specific and dose-responsive increases in APOBEC3B expression and activity, which could then be strongly suppressed by PKC or NF-κB inhibition. PKC activation caused the recruitment of RELB, but not RELA, to the APOBEC3B promoter, implicating noncanonical NF-κB signaling. Notably, PKC was required for APOBEC3B upregulation in cancer cell lines derived from multiple tumor types. By revealing how APOBEC3B is upregulated in many cancers, our findings suggest that PKC and NF-κB inhibitors may be repositioned to suppress cancer mutagenesis, dampen tumor evolution, and decrease the probability of adverse outcomes, such as drug resistance and metastasis.

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

  • Cell Line, Tumor
  • Cytidine Deaminase / biosynthesis*
  • Cytidine Deaminase / genetics
  • Humans
  • Minor Histocompatibility Antigens
  • NF-kappa B p50 Subunit / biosynthesis
  • NF-kappa B p52 Subunit / biosynthesis
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Papillomavirus Infections / pathology
  • Promoter Regions, Genetic / genetics
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Signal Transduction
  • Tetradecanoylphorbol Acetate / analogs & derivatives
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor RelA / antagonists & inhibitors
  • Transcription Factor RelA / metabolism*
  • Transcription Factor RelB / antagonists & inhibitors
  • Transcription Factor RelB / metabolism*
  • Transcriptional Activation

Substances

  • Minor Histocompatibility Antigens
  • NF-kappa B p50 Subunit
  • NF-kappa B p52 Subunit
  • NFKB1 protein, human
  • NFKB2 protein, human
  • RELA protein, human
  • RELB protein, human
  • Transcription Factor RelA
  • Transcription Factor RelB
  • phorbolol myristate acetate
  • Protein Kinase C
  • APOBEC3B protein, human
  • Cytidine Deaminase
  • Tetradecanoylphorbol Acetate