title: The PKC/NF-κB signaling pathway induces APOBEC3B expression in multiple human cancers.
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.
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Brandon
authors.initials: B
authors.lastname: Leonard
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: McCann
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Gabriel J
authors.initials: GJ
authors.lastname: Starrett
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Faculty of Medicine, University of British Columbia, Vancouver, Canada.
authors.forename: Leah
authors.initials: L
authors.lastname: Kosyakovsky
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Luengas
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Amy M
authors.initials: AM
authors.lastname: Molan
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Burns
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Medical School, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: McDougle
authors.affiliation: Protein Phosphorylation Laboratory, Francis Crick Institute, London, United Kingdom. Division of Cancer Studies, King's College London, London, United Kingdom.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Parker
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
authors.forename: William L
authors.initials: WL
authors.lastname: Brown
authors.affiliation: Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota. Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota. Howard Hughes Medical Institute, University of Minnesota, Minneapolis, Minnesota. rsh@umn.edu.
authors.forename: Reuben S
authors.initials: RS
authors.lastname: Harris
mesh_terms: D045744:Cell Line, Tumor; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D015778:Minor Histocompatibility Antigens; D052002:NF-kappa B p50 Subunit / Q000096:biosynthesis; D052003:NF-kappa B p52 Subunit / Q000096:biosynthesis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051841:Transcription Factor RelB / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D015778:Minor Histocompatibility Antigens; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; C489548:NFKB1 protein, human; C498206:NFKB2 protein, human; C498143:RELA protein, human; C497593:RELB protein, human; D051996:Transcription Factor RelA; D051841:Transcription Factor RelB; C016658:phorbolol myristate acetate; D011493:Protein Kinase C; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase; D013755:Tetradecanoylphorbol Acetate