The Francis Crick Institute
nihms728173.pdf (940.45 kB)

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

Download (940.45 kB)
journal contribution
posted on 2020-08-27, 14:17 authored by Brandon Leonard, Jennifer L McCann, Gabriel J Starrett, Leah Kosyakovsky, Elizabeth M Luengas, Amy M Molan, Michael B Burns, Rebecca M McDougle, Peter J Parker, William L Brown, Reuben S Harris
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.