JMJD8 is a positive regulator of TNF-induced NF-κB signaling

Abstract

TNF-induced signaling mediates pleiotropic biological consequences including inflammation, immunity, cell proliferation and apoptosis. Misregulation of TNF signaling has been attributed as a major cause of chronic inflammatory diseases and cancer. Jumonji domain-containing protein 8 (JMJD8) belongs to the JmjC family. However, only part of the family members has been described as hydroxylase enzymes that function as histone demethylases. Here, we report that JMJD8 positively regulates TNF-induced NF-κB signaling. Silencing the expression of JMJD8 using RNA interference (RNAi) greatly suppresses TNF-induced expression of several NF-κB-dependent genes. Furthermore, knockdown of JMJD8 expression reduces RIP ubiquitination, IKK kinase activity, delays IκBα degradation and subsequently blocks nuclear translocation of p65. In addition, JMJD8 deficiency enhances TNF-induced apoptosis. Taken together, these findings indicate that JMJD8 functions as a positive regulator of TNF-induced NF-κB signaling.

LY75 Ablation Mediates Mesenchymal-Epithelial Transition (MET) in Epithelial Ovarian Cancer (EOC) Cells Associated with DNA Methylation Alterations and Suppression of the Wnt/β-Catenin Pathway

“…Jmjd8 belongs to the family of JmjC domain-redox enzymes that catalyze protein hydroxylation or demethylation [32], as a role of Jmjd8 in regulating cellular metabolism and angiogenesis has been recently reported [33]. An oncogenic role of Jmjd8 as a positive regulator of TNF-induced NF-κB signaling in colorectal cancer has been described [34,35]; however, a recent study demonstrated that JMJD8 knockdown promotes cell proliferation and double-strand base (DSB) repair in lung and bone cancer cells, suggesting that Jmjd8 could represent a potential target for more effective tumor radio-and chemotherapies [36]. As a member of Wnt/β-catenin family, an oncogenic role for Wnt3 has been reported in different cancer types, including colorectal, gastric, breast, liver, and lung cancer [37][38][39][40][41]; yet a potential tumor-suppressor role for Wnt3 has been described in chronic lymphocytic leukemia, where decreased Wnt3 expression is associated with disease progression and worse prognosis [42].…”

JMJD8 is a novel endoplasmic reticulum protein with a JmjC domain

“…In our previous study, we showed that JMJD8 functions as a positive regulator of the TNF-induced NF-κB pathway 16 . To better understand the biological functions of JMJD8, we sought to identify the interacting partners of JMJD8.…”

“…revealed that JMJD8 localizes to the extranuclear region instead of the nucleus. Interestingly, we previously demonstrated that JMJD8 is a positive regulator of the TNF signaling pathway 16 . In addition, ubiquitinated NF-κB signaling components, including RIP1, Bcl10 and TRAF2, have been shown to be recruited to the ER, which is required for optimal activation of NF-κB 19 .…”

“…Recent studies have shown that JMJD8 is involved in angiogenesis and cellular metabolism through interacting with Pyruvate kinase M2 15 . It is also a positive regulator of the TNF-induced NF-κB signaling pathway 16 . In this study, we examined the subcellular localization and the biophysical and biochemical properties of JMJD8.…”

Hypoxia and Inflammation in Cancer, Focus on HIF and NF-кB

“…Furthermore, JMJD8 has been shown to positively regulate TNF induced NF-κB signalling, although the mechanism by which this occurs has not been elucidated [102]. These reports further highlight some known and potential crosstalk points between hypoxia and NF-κB.…”