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

Brandon Leonard,William L Brown,Peter J Parker,Jennifer L Mccann,Reuben S Harris,Rebecca M Mcdougle,Michael B Burns,Leah Kosyakovsky,Elizabeth M Luengas,Amy M Molan,Gabriel J Starrett

doi:10.1158/0008-5472.can-15-2171-t

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.

Highlights

Somatic mutations are essential for nearly every hallmark of cancer [1]
Our studies suggest a model in which PKCa activation signals through the noncanonical NF-kB pathway and results in the recruitment of RELB to the APOBEC3B gene and its transcriptional activation (Fig. 5)
protein kinase C (PKC) inhibitor studies with breast, head/neck, bladder, and ovarian cancer cell lines demonstrate that the PKC/NF-kB pathway contributes to the constitutively high levels of endogenous APOBEC3B associated with cancer mutagenesis

Summary

Introduction

Somatic mutations are essential for nearly every hallmark of cancer [1]. Mutations occur when DNA damage escapes repair. Cancer genome deep sequencing studies are confirming previously known sources of mutation as well as helping to discover new ones [2,3,4]. Established sources of mutation include UV light in skin cancer, tobacco carcinogens in lung cancer, and hydrolytic deamination of methyl-cytosine as a function of age in most cancers. One newly discovered source is the plant-derived dietary supplement aristolochic acid, which causes A-to-T transversion mutations in liver and bladder cancers [5]. A second and larger source of mutation is the APOBEC family of DNA cytosine deaminases, which cause signature C-to-T transition and C-toG transversion mutations in breast, head/neck, bladder, cervical, lung, and ovarian cancers [2,3,4, 6,7,8,9,10,11].

Methods

Results

Conclusion