期刊
ONCOGENE
卷 40, 期 5, 页码 937-950出版社
SPRINGERNATURE
DOI: 10.1038/s41388-020-01580-w
关键词
-
资金
- University of Macau [MYRG2019-00116-FHS, MYRG2017-00176-FHS]
The study identified BET inhibitors as selective drugs for SMAD4(-/-) CRC cells, inducing growth arrest through the reprogramming of the MYC-p21 axis.
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.
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