Abstract
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.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
