Telomere length dependent regulation of IL1R1 (Interleukin 1Receptor type I) by TRF2 (Telomere repeat binding factor 2) is crucial to TAM (tumor associated macrophage) infiltration in cancer cells

Abstract

TRF2 (Telomere Repeat Binding Factor 2) is a known component of the mammalian shelterin complex and is critical for telomere maintenance. However, recent findings suggest that TRF2 can associate with DNA outside of telomeres including several gene promoters. Our work shows that TRF2 can modulate transcription by inducing local epigenetics in a telomere length dependent manner. Herein, we present the first evidence that TRF2 can occupy the IL1R1 (Interleukin 1 Receptor Type 1) promoter by associating with promoter G-quadruplexes. TRF2 activates the IL1R1 promoter by primarily inducing H3K27ac by recruiting p300 Histone acetyl transferase to the promoter. As a consequence of TRF2 mediated activation of IL1R1, cells with high TRF2 have enhanced sensitivity to the pro-inflammatory cytokine IL1 beta and downstream activation of NF kappa B targets like IL6, IL8 and TNFα. As suggested by previous studies, the activation of the IL1 pathway might have implications in cancer progression by inducing the production of pro-inflammatory cytokines in the tumour microenvironment. Recent reports suggest the IL1R1- IL1 beta axis of paracrine and autocrine signaling are crucial to the maintenance of Tumor associated macrophages (TAM) and consequent suppression of immune response against cancer cells. Our work goes on to explore how TRF2 mediated upregulation of IL1R1 in cancer cells might have crucial implications in recruitment and maintenance of TAMs in the tumor micro-environment and its connection to telomere length of cancer cells.