Potent bromodomain and extraterminal domain inhibitor JAB-8263 suppresses MYC expression and exerts anti-tumor activity in colorectal cancer models

BACKGROUND The overexpression of the MYC gene plays an important role in the occurrence,development and evolution of colorectal cancer(CRC).Bromodomain and extraterminal domain(BET)inhibitors can decrease the function BET by recognizing acetylated lysine residues,thereby downregulating the expression of MYC.AIM To investigate the inhibitory effect and mechanism of a BET inhibitor on CRC cells.METHODS The effect of the BET inhibitor JAB-8263 on the proliferation of various CRC cell lines was studied by CellTiter-Glo method and colony formation assay.The effect of JAB-8263 on the cell cycle and apoptosis of CRC cells was studied by propidium iodide staining and Annexin V/propidium iodide flow assay,respectively.The effect of JAB-8263 on the expression of c-MYC,p21 and p16 in CRC cells was detected by western blotting assay.The anti-tumor effect of JAB-8263 on CRC cells in vivo and evaluation of the safety of the compound was predicted by constructing a CRC cell animal tumor model.RESULTS JAB-8263 dose-dependently suppressed CRC cell proliferation and colony formation in vitro.The MYC signaling pathway was dose-dependently inhibited by JAB-8263 in human CRC cell lines.JAB-8263 dose-dependently induced cell cycle arrest and apoptosis in the MC38 cell line.SW837 xenograft model was treated with JAB-8263(0.3 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P<0.001).The MC38 syngeneic murine model was treated with JAB-8263(0.2 mg/kg for 29 d),and the average tumor volume was significantly decreased compared to the vehicle control group(P=0.003).CONCLUSION BET could be a potential effective drug target for suppressing CRC growth,and the BET inhibitor JAB-8263 can effectively suppress c-MYC expression and exert anti-tumor activity in CRC models.

Inhibition of BET selectively eliminates undifferentiated pluripotent stem cells

Embryonic stem cells （ESCs） maintain their cellular identity through the systematic regulation of master transcription factors and chromatin remodeling complexes. Recent work has shown that the unusually large-scale enhancers-namely super-enhancers （SEs）, on which BRD4, a member of the bromodomain and extraterminal domain （BET） family is highly enriched-could regulate pluripotency-related transcrip- tion factors. Moreover, inhibition of BRD4 binding on SEs has been shown to induce the differentiation of ESCs. However, the underlying mechanism of BRD4 inhibition-mediated stern cell differentiation remains elusive. Here we show that both mouse and human ESCs lose their capacity for self-renewal upon treat- ment with JQ1, a selective inhibitor of BET family including BRD4, with rapid suppression of pluripotency-associated genes. Notably, a high concentration of JQI could selectively eliminate ESCs via apoptosis, without affecting the functionality of differentiated somatic cells from ESCs, suggesting that inhibition of BET may have a beneficial effect on the development of pluripotent stem cell-based cell therapy.