Abstract
It has long been known that patients suffering from inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). The innate immune system of host cells provides a first-line defence against pathogenic infection, whereas uncontrolled inflammatory response under homeostatic conditions usually leads to pathological consequences, as exemplified by the chronic inflammation of IBD. The key molecules and pathways keeping innate immunity in check are still poorly defined. Here, we report that chromatin remodeler polybromo-1 (PBRM1) is a repressor of innate immune signaling mediated by RIG-I-like receptors (RLRs). Knock-down of PBRM1 in colon cancer cells increased the expression of two receptor genes (RIG-I and MDA5) and upregulated interferon- and inflammation-related gene signatures. Moreover, the innate immune signal stimulated by dsRNA viral mimic was exaggerated by PBRM1 suppression. PBRM1 cooperated with polycomb protein EZH2 to directly bind the cis-regulatory elements of the RIG-I and MDA5 genes, thereby suppressing their transcription. Moreover, upregulation of RIG-I and MDA5 is required for IFN response activation induced by PBRM1 silencing. TRIM25, a protein stimulated by the RLR pathway and interferon production, physically interacted with PBRM1 and induced PBRM1 protein destabilization by promoting its ubiquitination. These findings reveal a PBRM1-RLR regulatory circuit that can keep innate immune activity at a minimal level in resting cells and also ensure a robust inflammatory response in case of pathogen invasion. PBRM1 was found to be downregulated in primary tissues from patients with CRC or IBD, and its expression correlated negatively with that of RLR genes and ISGs (interferon-stimulating genes) in CRC samples. Lower PBRM1 expression was associated with advanced pathologic grade and poorer survival of CRC patients.
from #ORL-AlexandrosSfakianakis via ola Kala on Inoreader http://ift.tt/2xmYZtC
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