Abstract
Under some conditions, nuclear factor-κB (NF-κB) has a pro-apoptotic role, but the mechanisms underlying this function remain unclear. This study demonstrated that NF-κB directly binds to CASP9 and miR1276 in tumor necrosis factor α (TNFα)-treated HeLa and HepG2 cells. NF-κB upregulated CASP9 expression, whereas downregulated miR1276 expression in the TNFα-treated cells. The miR1276 repressed CASP9 expression in both cells. As a result, a typical NF-κB-mediated coherent feed-forward loop was formed in the TNFα-treated cells. It was proposed that the NF-κB-mediated loop may contribute to cell apoptosis under certain conditions. This opinion was supported by the following evidence: TNFα promoted the apoptosis of HeLa and HepG2 cells induced by doxorubicin (DOX). CASP9 was significantly upregulated and activated by TNFα in the DOX-induced cells. Moreover, a known inhibitor of CASP9 activation significantly repressed the TNFα promotion of apoptosis induced by DOX. These findings indicate that CASP9 is a new mediator of the NF-κB pro-apoptotic pathway, at least in such conditions. This study therefore provides new insights into the pro-apoptotic role of NF-κB. The results also shed new light on the molecular mechanism underlying TNFα-promotion of cancer cells apoptosis induced by some anticancer drugs such as DOX.
Highlights
Nuclear factor-κB (NF-κB) is an inducible transcription factor (TF) [1]
We find that the regulation of CASP9 through NF-κB-mediated feed-forward loop (FFL) plays a pro-apoptotic role in the tumor necrosis factor α (TNFα)-promoted apoptosis of cancer cells induced by DOX
Based on the importance of CASP9 for cell apoptosis and the current acknowledged anti-apoptotic function of NF-κB in cancer, we think it is necessary to study whether NF-κB regulates the CASP9 gene, which may provide new insight into the potential pro-apoptotic role of this TF
Summary
Nuclear factor-κB (NF-κB) is an inducible transcription factor (TF) [1]. After exposure of cells to inducers such as tumor necrosis factor α (TNFα), the inhibition of nuclear translocation and DNA-binding activity of NF-κB by IκB proteins is removed [1,2]. The activated NF-κB binds to κB sites in genomic DNA and regulates the transcription of its target genes in these cells [1]. NF-κB regulates the expressions of microRNAs (miRNAs) at the transcriptional level [3]. MiRNAs are critical regulators of gene expression, which act as post-transcriptional repressors by binding to the 3 untranslated regions (UTRs) of their target genes [3]. The interplay between NF-κB and its regulated miRNAs creates positive or negative feedback loops and regulatory networks, which can control cell fate, such as cell apoptosis [3]
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