Abstract
Inhibition of BET bromodomains (BRDs) has emerged as a promising cancer therapeutic strategy. Accordingly, inhibitors of BRDs such as JQ1 have been actively developed and some have reached clinical testing. However, the mechanisms by which this group of inhibitors exerts their anticancer activity, including induction of apoptosis, have not been fully elucidated. This report reveals a previously uncovered activity of JQ1 in inducing c-FLIP degradation and enhancing TRAIL-induced apoptosis. JQ1 potently decreased c-FLIP (both long and short forms) levels in multiple cancer cell lines without apparently increasing the expression of DR5 and DR4. Consequently, JQ1, when combined with TRAIL, synergistically induced apoptosis; this enhanced apoptosis-inducing activity could be abolished by enforced expression of ectopic FLIPL or FLIPS. Hence it appears that JQ1 decreases c-FLIP levels, resulting in enhancement of TRAIL-induced apoptosis. Inhibition of proteasome with MG132 prevented JQ1-induced c-FLIP reduction. Moreover, JQ1 decreased c-FLIP stability. Therefore, JQ1 apparently decreases c-FLIP levels through facilitating its proteasomal degradation. Genetic inhibition of either BRD4 or c-Myc by knocking down their expression failed to mimic JQ1 in decreasing c-FLIP and enhancing TRAIL-induced apoptosis, suggesting that JQ1 induces c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 or c-Myc inhibition. In summary, our findings in this study highlights a novel biological function of JQ1 in modulating apoptosis and warrant further study of the potential treatment of cancer with the JQ1 and TRAIL combination.
Highlights
The bromodomain (BRD) and extra-terminal domain (BET) family is comprised of four proteins: BRD2, BRD3, BRD4, and BRDT, which perform diverse roles in regulating gene transcription
In an effort to identify agents that suppress Cellular FLICE-inhibitory protein (c-FLIP) expression, we found that JQ1 at a range of 1 to 5 μM effectively decreased the levels of c-FLIP including both long (FLIPL) and short (FLIPS) forms in the 3 tested JQ1-senstive non-small cell lung cancer (NSCLC) cell lines, H157, H1299 and A549 (Figures. 1B and 1C)
We found that c-Myc small interfering RNA (siRNA) effectively decreased c-Myc expression, but failed to prevent c-FLIP reduction induced by JQ1 the basal levels of c-FLIP were elevated by c-Myc knockdown in A549 cells (Figure 7), suggesting that JQ1-induced c-FLIP reduction is unlikely secondary to c-Myc upregulation in these cell lines
Summary
The bromodomain (BRD) and extra-terminal domain (BET) family is comprised of four proteins: BRD2, BRD3, BRD4, and BRDT, which perform diverse roles in regulating gene transcription. These BET family proteins have been identified in oncogenic rearrangements, generating highly oncogenic fusion proteins, and in regulating transcription of several oncogenes, such as c-Myc and Bcl-2. In the past few years, several small molecule inhibitors that target BET family proteins, BRD4, have been developed These inhibitors have been actively used either as therapeutic agents or as research tools in many preclinical studies and some of them have advanced to testing in clinical trials [1, 2]. The majority of studies have shown that the therapeutic effect of BET BRD inhibitors is attributed to targeting BRD4, rather than the other BET proteins [2]
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