Telomerase directly regulates NF-κB-dependent transcription

Abstract

Although elongation of telomeres is thought to be the prime function of reactivated telomerase in cancers, this activity alone does not account for all of the properties that telomerase reactivation attributes to human cancer cells. Here, we uncover a link between telomerase and NF-κB, a master regulator of inflammation. We observe that while blocking NF-κB signalling can inhibit effects of telomerase overexpression on processes relevant to transformation, increasing NF-κB activity can functionally substitute for reduced telomerase activity. Telomerase directly regulates NF-κB-dependent gene expression by binding to the NF-κB p65 subunit and recruitment to a subset of NF-κB promoters such as those of IL-6 and TNF-α, cytokines that are critical for inflammation and cancer progression. As NF-κB can transcriptionally upregulate telomerase levels, our findings suggest that a feed-forward regulation between them could be the key mechanistic basis for the coexistence of chronic inflammation and sustained telomerase activity in human cancers.

Telomerase stimulates ribosomal DNA transcription under hyperproliferative conditions

“…We show that telomerase binds to rDNA and stimulates transcription in a regenerative-or growth signal-dependent manner. Our results are consistent with recent findings on the binding of TERT to extratelomeric motifs, suggesting a novel function of telomerase as a transcriptional co-regulator of Wnt or NF-kB signalling 3,4 . TERT binding to the TCF3 binding sites was observed in HeLa cells and proliferating gut epithelium 3 .…”

“…In our study, we observe non-oncogenic rDNA binding of telomerase when resting hepatocytes enter a proliferative mode. This observation may reflect a physiological response to an elevated need for ribosomes and is supported by the observation of Ghosh et al 4 that the NF-kB pathway is dampened in telomerase-knockout animals, indicating a physiological role for telomerase in gene regulation in vivo. It is interesting that mice with a hypomorphic DKC1 (dyskeratosis congenita 1) mutant protein show dysregulated ribosome function 39 .…”

“…Interestingly, Ghosh et al 4 also found that functional telomerase is required to regulate NF-kB signalling. The authors observed that the telomerase holoenzyme is important for NF-kB-dependent gene expression.…”

“…Recent studies provided some insight into the mechanisms by which TERT may contribute to tumorigenic conversion of cells that extend beyond its canonical function. These studies demonstrated that telomerase can act as a transcriptional co-activator to regulate the Wnt pathway or can directly regulate NF-kBdependent transcription 3,4 .…”

Rap1 induces cytokine production in pro-inflammatory macrophages through NFκB signaling and is highly expressed in human atherosclerotic lesions

“…[25][26][27][28] Given the involvement of NFkB signaling in atherosclerosis, LPS was used to activate it and stimulate the production of NFkBdependent pro-inflammatory cytokines. 29,30 Indeed, LPS caused a sustained activation of p65 in THP-1 macrophages ( Fig. 2A).…”