Published online Dec 15, 2022. doi: 10.4251/wjgo.v14.i12.2340
Peer-review started: August 11, 2022
First decision: October 5, 2022
Revised: October 17, 2022
Accepted: November 16, 2022
Article in press: November 16, 2022
Published online: December 15, 2022
Processing time: 123 Days and 2.8 Hours
Bromodomain-containing protein 4 (BRD4) as a transcriptional regulator promotes tumor development. Thus, targeting of BRD4 has recently emerged as a promising anti-cancer therapeutic strategy. Although it has been reported that BRD4 inhibition repressed esophageal squamous cell carcinoma (ESCC) cell proliferation, the role of BRD4 inhibition in ESCC cell migration remains unclear.
To explore the role of targeting BRD4 on ESCC cell migration for developing BRD4 inhibitor combination therapies when clinical application of BRD4 inhibitor as anti-cancer therapy.
To explore the effect of BRD4 inhibition on ESCC cell migration and the potential mechanism.
Human ESCC cell lines KYSE-450 and KYSE-150 were cultured. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-terazolium bromide assay was performed to examine cell proliferation and transwell assay was conducted to cell migration. JQ1 was used to inhibit BRD4 function and siBRD4 was transfected into ESCC cells to knockdown endogenous BRD4. GFP-RFP-LC3 adenovirus was infected into ESCC cells to evaluate the effect of JQ1 on autophagy. Western blot was performed to determine the protein levels of BRD4, E-cadherin, vimentin, AMP-activated protein kinase (AMPK), and p-AMPK.
JQ1 inhibited ESCC cell proliferation, but JQ1 or knockdown of BRD4 promoted ESCC cell migration as well as epithelial-mesenchymal transition (EMT). Application of JQ1 increased autophagosomes and autolysosomes in ESCC cells and enhanced level of LC3-II and AMPK phosphorylation in a dose-dependent manner. The autophagy inhibitor 3-MA blocked JQ1-induced cell migration and EMT.
Inhibition of BRD4 promotes ESCC cell migration and EMT mediated by activation of autophagy.
The migration-promoting effect should be carefully considered when applying JQ1 or targeting BRD4 as an anti-cancer approach. JQ1, in combination with an autophagy inhibitor, might be a new therapeutic strategy to overcome the effects of JQ1 on cancer cell migration.