OGG1 as an Epigenetic Reader Affects NFκB: What This Means for Cancer

Abstract

8-oxoguanine glycosylase 1 (OGG1), which was initially identified as the enzyme that catalyzes the first step in the DNA base excision repair pathway, is now also recognized as a modulator of gene expression. What is important for cancer is that OGG1 acts as a modulator of NFκB-driven gene expression. Specifically, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, such as NFκB to their cognate sites, enabling the expression of cytokines and chemokines, with ensuing recruitment of inflammatory cells. Recently, we highlighted chief aspects of OGG1 involvement in regulation of gene expression, which hold significance in lung cancer development. However, OGG1 has also been implicated in the molecular underpinning of acute myeloid leukemia. This review analyzes and discusses how these cells adapt through redox-modulated intricate connections, via interaction of OGG1 with NFκB, which provides malignant cells with alternative molecular pathways to transform their microenvironment, enabling adjustment, promoting cell proliferation, metastasis, and evading killing by therapeutic agents.

Keywords: EMT; NFκB; OGG1; acute myeloid leukemia; cancer stem cells; gene regulation; innate immunity; lung cancer; microenvironment; oxidant stress.

Figure 1

The proposed role of OGG1 in regulating gene expression related to tumor cell proliferation. In response to growth factors, hormones, metabolites, or environmental factors ROS are generated by NADPH oxidases and mitochondrial respiratory complexes. ROS signaling is crucial for activating growth factors (e.g., TGFβ1), transacting factors (e.g., NFκB, AP-1), and for modifying DNA bases (e.g., guanine → 8-oxoGua, an epigenetic mark). ROS also induce the oxidation of OGG1 at cysteine residues, inhibiting its glycosylase activity without affecting its ability to recognize/interact with intrahelical 8-oxoGua and the complementary cytosine.OGG1’s interaction with 8-oxoGua induces topographical rearrangements in DNA, resulting in an approximately 70-degree bending. This transient topographical change facilitates the DNA occupancy of transcription factors (e.g., SMADs, AP-1, HIF-1, NFκB) and components of the transcriptional machinery. Abbreviations: TGFβ—transforming growth factor beta; GF—growth factor; NOX—NADPH oxidoreductase; ROS—reactive oxygen species; SMAD—mothers against decapentaplegic homolog; AP-1—Jun activation-domain binding protein; HIF—hypoxia inducible factor; NFκB—nuclear factor kappa B. Created using Bio-Render: https://app.biorender.com (accessed on 9 September 2023).

Figure 2

ROS that exceed an OGG1 variant-specific threshold halt OGG1 enzymatic activity temporarily to modulate the function of transcription factor NFκB. Despite evidence for transcription factor modulation by enzymatically active OGG1, here, we present the type of OGG1 reader activity that affects the microenvironment of a given cell through NFκB modulation. NFκB activates inflammation and this in turn can increase ROS levels. The positive transcription activation feedback loop generated in this manner can have a substantial impact in host tissue due to sustained expression of inflammatory mediators and disruption of physiological homeostatic function.

Figure 3

A proposed model for two basic phenotypes of AML stem-like cells that may also coexist in a form of dynamic equilibrium that is regulated by the metabolic state of their microenvironment.