1. The PKC/NF-κB signaling pathway induces APOBEC3B expression in multiple human cancers.
- Author
-
Leonard B, McCann JL, Starrett GJ, Kosyakovsky L, Luengas EM, Molan AM, Burns MB, McDougle RM, Parker PJ, Brown WL, and Harris RS
- Subjects
- Cell Line, Tumor, Cytidine Deaminase genetics, Humans, Minor Histocompatibility Antigens, NF-kappa B p50 Subunit biosynthesis, NF-kappa B p52 Subunit biosynthesis, Neoplasms genetics, Papillomavirus Infections pathology, Promoter Regions, Genetic genetics, Protein Kinase C antagonists & inhibitors, Protein Kinase C genetics, Signal Transduction, Tetradecanoylphorbol Acetate analogs & derivatives, Tetradecanoylphorbol Acetate pharmacology, Transcription Factor RelA antagonists & inhibitors, Transcription Factor RelB antagonists & inhibitors, Transcriptional Activation, Cytidine Deaminase biosynthesis, Neoplasms metabolism, Protein Kinase C metabolism, Transcription Factor RelA metabolism, Transcription Factor RelB metabolism
- 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., (©2015 American Association for Cancer Research.)
- Published
- 2015
- Full Text
- View/download PDF