LAUSR

The tumor suppressor SMAD4 is frequently mutated in colorectal cancer (CRC). However, no effective targeted therapies exist for CRC with SMAD4 loss. Here, we employed a synthetic lethality drug screening in isogenic SMAD4+/+ and SMAD4−/− HCT116 CRC cells and found that bromodomain and extra-terminal motif (BET) inhibitors, as selective drugs for the growth of SMAD4−/− HCT116 cells. BET inhibition selectively induced G1 cell cycle arrest in SMAD4−/− cells and this effect was accompanied by the reprogramming of the MYC-p21 axis. Mechanistically, SMAD4 is a transcription repressor of MYC, and MYC in turn represses p21 transcription. SMAD4−/− cells lost MYC repression ability, thereby causing the cells addicted to the MYC oncogenic signaling. BET inhibition significantly reduced MYC level and restored p21 expression in SMAD4−/− cells, inducing the selective growth arrest. The ectopic overexpression of MYC or the silencing of p21 could rescue the BET inhibitor-induced growth arrest in SMAD4−/− cells, verifying this model. Tumor xenograft mouse experiments further demonstrated the synthetic lethality interaction between BET and SMAD4 in vivo. Taken together, our data suggest that BET could be a potential drug target for the treatment of SMAD4-deficient CRC.