Bromodomain and Extraterminal (BET) protein inhibition suppresses tumor progression and inhibits HGF-MET signaling through targeting cancer-associated fibroblasts in colorectal cancer.

OBJECTIVE:Colorectal cancer (CRC) is one of the leading causes of cancer-related mortality. The bromodomain and extra-terminal domain (BET) inhibitors suppresses the gene expressions of various oncogenes and shows a good efficacy in the preclinical CRC models. We investigate the mechanism of action of BET inhibitors in CRC. METHODS:The effect of BET inhibitor (JQ1) on the HGF-MET signaling was assessed by qPCR, western blot and immunohistochemical staining in CRC and cancer-associated fibroblasts (CAFs). The effect of JQ1 on the CAFs was investigated using the primary CAFs derived from CRC tissues and induced-CAFs derived from isolating foreskin fibroblasts. The effect of JQ1 on the gene expression profile of CAFs was explored by RNA-sequence, qPCR and bioinformatic analysis. RESULTS:JQ1 decreased the mRNA and protein levels of MET in CRC cells and downregulated the mRNA and protein levels of HGF in both CRC cells and CAFs. JQ1 attenuated the pro-migratory activity of CAFs through downregulation of HGF expression in CAFs. Meanwhile, JQ1 also reduced the ability of contracting collagen gels, decreased the cell proliferation, induced G1 arrest and repressed the pro-inflammatory gene expressions in CAFs. MYC expression was suppressed by JQ1 in CAFs. Knockdown of MYC induced G1 arrest in CAFs. CONCLUSION:Our results demonstrate the inhibitory effect of BET inhibition on the HGF-MET signaling and the pro-tumor activity of CAFs, revealing a new mechanism by which BET inhibition suppresses CRC progression.