A sustained small increase in NOD1 expression promotes ligand-independent oncogenic activity

Abstract

Abstract Small genetically-determined differences in transcription are implicated in complex disease but the mechanisms by which small changes in gene expression impact the origin of complex disease are unknown. Recent GWAS fine-mapping studies show that many causal alleles for complex immune-related diseases lie in non-coding regions of genes, generating expression quantitative trait loci (eQTLs), with the extent of expression variation between susceptible and resistant genotypes often in the 1.5–3 fold range. Concurrently, systems-level studies across several cancer types suggest a regulatory organization in which disease-promoting genomic mutations lie upstream of functional master regulator proteins, a change in whose expression by 1.5–3 fold is responsible for propagating a tumor cell state. Here we show that a persistent small (~1.5 fold) increase in expression of the innate sensor NOD1 (Nucleotide-binding Oligomerization Domain-containing protein 1) precipitates large cancer-promoting changes in cell state in the absence of ligand-driven activity. A ~1.2–1.4-fold increase in NOD1 protein concentration by loss of microRNA regulation sensitizes cells to ligand-induced inflammation with an additional slight increase leading to ligand-independent NOD1 activation that upregulates the expression of proto-oncogenes and is linked to poor prognosis in gastric cancer. Our data show that tight expression regulation of NOD1 prevents this sensor from exceeding a physiological switching checkpoint that promotes persistent inflammation and oncogene expression and reveal the impact of a single small quantitative change in cell state on cancer.