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Bromodomain and extra-terminal motif (BET) inhibition is synthetic lethal with loss of SMAD4 in colorectal cancer cells via restoring the loss of MYC repression

Oncogene volume 40, pages 937–950 (2021)Cite this article

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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.

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Fig. 1: Epigenetics compound library screening identifies that SMAD4-deficient CRC cells are hypersensitive to BETi.
Fig. 2: BETi induces G1 cell cycle arrest selectively in SMAD4−/− HCT116 cells.
Fig. 3: BET inhibition led to cell growth arrest by targeting MYC-p21 axis in HCT116 SMAD4−/− cells.
Fig. 4: The SMAD4/BET synthetic lethality is broadly applicable in CRC and pancreatic cancer.
Fig. 5: BET inhibition is synthetic lethal with loss of SMAD4 in vivo.
Fig. 6: A working model for the proposed mechanism driving the synthetic lethality between SMAD4 and BET.

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Acknowledgements

We thank to the members of the FHS Animal Facility, Biological Imaging and Stem Cell Core, and Genomics, Bioinformatics and Single Cell Core at the University of Macau for experimental and technical supports. This study was supported by the Multi-Year Research Grants (MYRG2019-00116-FHS and MYRG2017-00176-FHS) to JSS from the University of Macau.

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  1. Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR, China

    Changxiang Shi, Eun Ju Yang, Yifan Liu, Pui Kei Mou, Guowen Ren & Joong Sup Shim

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Shi, C., Yang, E.J., Liu, Y. et al. Bromodomain and extra-terminal motif (BET) inhibition is synthetic lethal with loss of SMAD4 in colorectal cancer cells via restoring the loss of MYC repression. Oncogene 40, 937–950 (2021). https://doi.org/10.1038/s41388-020-01580-w

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