Abstract
Bromodomain (BRD), a protein module that recognizes acetylated lysine residues on histones and other proteins, has recently emerged as a promising therapeutic target for human diseases such as cancer. While most of the studies have been focused on inhibitors against BRDs of the bromo- and extra-terminal domain (BET) family proteins, non-BET family BRD inhibitors remain largely unexplored. Here, we investigated a potential anticancer activity of the recently developed non-BET family BRD inhibitor NVS-CECR2-1 that targets the cat eye syndrome chromosome region, candidate 2 (CECR2). We show that NVS-CECR2-1 inhibits chromatin binding of CECR2 BRD and displaces CECR2 from chromatin within cells. NVS-CECR2-1 exhibits cytotoxic activity against various human cancer cells, killing SW48 colon cancer cells in particular with a submicromolar half maximum inhibition value mainly by inducing apoptosis. The sensitivity of the cancer cells to NVS-CECR2-1 is reduced by CECR2 depletion, suggesting that NVS-CECR2-1 exerts its activity by targeting CECR2. Interestingly, our data show that NVS-CECR2-1 also kills cancer cells by CECR2-independent mechanism. This study reports for the first time the cancer cell cytotoxic activity for NVS-CECR2-1 and provides a possibility of this BRD inhibitor to be developed as an anticancer therapeutic agent.
Highlights
Bromodomain (BRD), a protein module that recognizes acetylated lysine residues on histones and other proteins, has recently emerged as a promising therapeutic target for human diseases such as cancer
We found that NVS-CECR2-1 has a strong cytotoxic activity on various human cancer cells, killing SW48 colon cancer cells in particular with a submicromolar value of half maximum inhibitory concentration ( IC50) by increasing apoptosis
Immunoblot analysis showed that CECR2 BRD roughly distributed into the both fractions and this distribution largely shifted to the chromatinunbound fractions with the CECR2-BRD band in the chromatin-bound fraction barely detected (Fig. 1b, lanes 1, 2, 5 and 6), indicating that NVS-CECR2-1 inhibited the chromatin binding of CECR2 BRD
Summary
Bromodomain (BRD), a protein module that recognizes acetylated lysine residues on histones and other proteins, has recently emerged as a promising therapeutic target for human diseases such as cancer. We investigated a potential anticancer activity of the recently developed non-BET family BRD inhibitor NVS-CECR2-1 that targets the cat eye syndrome chromosome region, candidate 2 (CECR2). This study reports for the first time the cancer cell cytotoxic activity for NVS-CECR2-1 and provides a possibility of this BRD inhibitor to be developed as an anticancer therapeutic agent. The human genome encodes 61 BRDs present in 46 distinct proteins, many of which are chromatin regulators, such as chromatin remodeler and histone modifier, that function in a wide array of biological processes Despite of their diversity of sequences, all BRDs share a conserved fold comprising left-handed four helix bundles linked by the ZA and BC loops, which forms a central deep and narrow hydrophobic cavity for the docking site of acetyl-lysine moiety. We performed analysis of CECR2 gene expression in colorectal cancer tissues using several online databases and discussed the significance of the results
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