Bromodomain and extra terminal
domain (BET) proteins function as epigenetic signaling factors that associate
with acetylated histones and facilitate transcription of target genes.
Inhibitors targeting the activity of BET proteins have shown potent
antiproliferative effects in hematological cancers through the suppression of c-MYC
and downstream target genes. However, as the epigenetic landscape of a cell
varies drastically depending on lineage, transcriptional coactivators such as
BETs would be expected to have different targets in cancers derived from
different cells of origin, and this may influence the activity and mechanism of
action of BET inhibitors. To test this hypothesis, we treated a panel of lung
adenocarcinoma (LAC) cell lines with the BET inhibitor JQ1 and found that a
subset is acutely susceptible to BET inhibition. In contrast to blood tumors,
we show that LAC cells are inhibited by JQ1 through a mechanism independent of
c-MYC down-regulation. Through gene expression profiling, we discovered that
the oncogenic transcription factor FOSL1 and its targets are suppressed by JQ1
in a dose-dependant manner. Knockdown of BRD4 also decreased FOSL1 levels, and
inhibition of FOSL1 phenocopied the effects of JQ1 treatment, suggesting that
loss of this transcription factor may be partly responsible for the cytotoxic
effects of BET inhibition in LAC cells, although ectopic expression of FOSL1
alone did not rescue the phenotype. Together, these findings suggest that BET
inhibitors may be useful in solid tumors and that cell-lineage-specific
differences in transcriptional targets of BETs may influence the activity of
inhibitors of these proteins in different cancer types.
Source: Sensitivity
of human lung adenocarcinoma cell lines to targeted inhibition of BET
epigenetic signaling proteins. Lockwood WW, Zejnullahu K, Bradner JE, Varmus H
(william.lockwood@nih.gov). Proc
Natl Acad Sci U S A. 2012 Nov 5.
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