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

Autor: Yifan Liu, Guowen Ren, Joong Sup Shim, Changxiang Shi, Pui Kei Mou, Eun Ju Yang
Rok vydání: 2020
Předmět:
0301 basic medicine
Cyclin-Dependent Kinase Inhibitor p21
Cancer Research
animal structures
Antineoplastic Agents
Apoptosis
Synthetic lethality
Biology
Proto-Oncogene Proteins c-myc
03 medical and health sciences
Mice
0302 clinical medicine
Cell Line
Tumor
Genetics
Gene silencing
Animals
Humans
Gene Silencing
neoplasms
Molecular Biology
Psychological repression
Cell Proliferation
Smad4 Protein
Regulation of gene expression
Proteins
HCT116 Cells
Xenograft Model Antitumor Assays
digestive system diseases
Bromodomain
Gene Expression Regulation
Neoplastic
030104 developmental biology
Cell culture
030220 oncology & carcinogenesis
embryonic structures
Cancer research
biological phenomena
cell phenomena
and immunity
Colorectal Neoplasms
Synthetic Lethal Mutations
G1 phase
Reprogramming
Signal Transduction
Zdroj: Oncogene. 40(5)
ISSN: 1476-5594
Popis: 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.
Databáze: OpenAIRE
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