NF‐κB/NKILA signaling modulates the anti‐cancerous effects of EZH2 inhibition

Abstract

A wealth of evidence supports the broad therapeutic potential of NF‐κB and EZH2 inhibitors as adjuvants for breast cancer treatment. We contribute to this knowledge by elucidating, for the first time, unique regulatory crosstalk between EZH2, NF‐κB and the NF‐κB interacting long non‐coding RNA (NKILA). We define a novel signaling loop encompassing canonical and non‐canonical actions of EZH2 on the regulation of NF‐κB/NKILA homeostasis, with relevance to breast cancer treatment. We applied a respective silencing approach in non‐transformed breast epithelial cells, triple negative MDA‐MB‐231 cells and hormone responsive MCF‐7 cells, and measured changes in EZH2/NF‐κB/NKILA levels to confirm their interdependence. We demonstrate cell line‐specific fluctuations in these factors that functionally contribute to epithelial‐to‐mesenchymal transition (EMT) remodelling and cell fate response. EZH2 inhibition attenuates MDA‐MB‐231 cell motility and CDK4‐mediated MCF‐7 cell cycle regulation, while inducing global H3K27 methylation and an EMT phenotype in non‐transformed cells. Notably, these events are mediated by a cell‐context dependent gain or loss of NKILA and NF‐κB. Depletion of NF‐κB in non‐transformed cells enhances their sensitivity to growth factor signaling and suggests a role for the host microenvironment milieu in regulating EZH2/NF‐κB/NKILA homeostasis. Taken together, this knowledge critically informs the delivery and assessment of EZH2 inhibitors in breast cancer.

PARP1 and PRC2 double deficiency promotes BRCA‐proficient breast cancer growth by modification of the tumor microenvironment

“…In contrast to the studies mentioned above, which implicate PARP1 and EZH2 in canonical NF-jB signaling via single gene knockdowns or pharmacological inhibitor experiments, we did not observe any significant changes in NF-jB signaling upon single gene depletion. Our results, however, are consistent with a very recent study demonstrating that inhibition of EZH2's enzymatic activity in the same MDA231 cell line used in our study did not affect nuclear RELA levels [47]. We speculate that EZH2 or PARP1 single gene depletion renders BRCA-proficient BCCs vulnerable to NF-jB pathway activation upon depletion of the second gene.…”

Scutellarein induces apoptosis and inhibits proliferation, migration, and invasion in ovarian cancer via inhibition of EZH2/FOXO1 signaling

“…An association between NF-κB and EZH2 in the progression of cancer has been reported frequently, with the suggestion that phosphorylated EZH2 binds and methylates NF-κB, which then leads to the proliferation of cells. [38,39] In this study, scutellarein treatment reduced the expression level of EZH2 in OC cells, which is in agreement with the studies that implicate EZH2 and NF-κB in the progression of OC. [12,30] FOXO1 is a transcription factor that negatively regulates the PI3K/AKT signaling pathway.…”

Chronic Inflammation Pathway NF-κB Cooperates with Epigenetic Reprogramming to Drive the Malignant Progression of Glioblastoma

“…Mechanistically, EZH2 represses SOX9 gene expression and inactivation causes derepression of SOX9, a transcriptional regulator of TNFRSF11A, which in turn is a receptor activator of NF-κB 52 . In addition, EZH2 has also been demonstrated to bind to NKILA and disrupt the reciprocal negative feedback inhibition between NKILA and NF‐κB 53 .…”