Co-inhibition of BET proteins and NF-κB as a potential therapy for colorectal cancer through synergistic inhibiting MYC and FOXM1 expressions
| العنوان: | Co-inhibition of BET proteins and NF-κB as a potential therapy for colorectal cancer through synergistic inhibiting MYC and FOXM1 expressions |
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| المؤلفون: | Chen-Ying Liu, Long Cui, Yuji Huang, Tingyu Wu, Zhehui Zhu, Wei Chen, Zhenyu Huang, Yun Liu, Peng Du, Yili Yang, Guanghui Wang |
| المصدر: | Cell Death and Disease, Vol 9, Iss 3, Pp 1-13 (2018) Cell Death & Disease |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Oncogene Protein p55(v-myc), 0301 basic medicine, Cancer Research, Angiogenesis, Immunology, Mice, Nude, Antineoplastic Agents, Article, Bortezomib, Proto-Oncogene Proteins c-myc, Mice, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Cell Line, Tumor, medicine, Animals, Humans, lcsh:QH573-671, Gene knockdown, lcsh:Cytology, Forkhead Box Protein M1, NF-kappa B, Nuclear Proteins, Drug Synergism, NF-κB, Azepines, Cell Cycle Checkpoints, Cell Biology, Triazoles, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, CTGF, IκBα, 030104 developmental biology, chemistry, Cell culture, FOXM1, Cancer research, Female, Colorectal Neoplasms, medicine.drug |
| الوصف: | The bromodomain and extra-terminal domain inhibitors (BETi) are promising epigenetic drugs for the treatment of various cancers through suppression of oncogenic transcription factors. However, only a subset of colorectal cancer (CRC) cells response to BETi. We investigate additional agents that could be combined with BETi to overcome this obstacle. JQ1-resistant CRC cells were used for screening of the effective combination therapies with JQ1. RNA-seq was performed to explore the mechanism of synergistic effect. The efficacy of combinational treatment was tested in the CRC cell line- and patient-derived xenograft (PDX) models. In BETi-sensitive CRC cells, JQ1 also impaired tumor angiogenesis through the c-myc/miR-17-92/CTGF+THBS1 axis. CTGF knockdown moderately counteracted anti-angiogenic effect of JQ1 and led to partially attenuated tumor regression. JQ1 decreased c-myc expression and NF-κB activity in BETi-sensitive CRC cells but not in resistant cells. Bortezomib synergistically sensitized BETi-resistant cells to the JQ1 treatment, and JQ1+Bortezomib induced G2/M arrest in CRC cells. Mechanistically, inhibition of NF-κB by Bortezomib or NF-κB inhibitor or IKK1/2 siRNA all rendered BETi-resistant cells more sensitive to BETi by synergistic repression of c-myc, which in turn induces GADD45s’ expression, and by synergistic repression of FOXM1 which in turn inhibit G2/M checkpoint genes’ expression. Activation of NF-κB by IκBα siRNA induced resistance to JQ1 in BETi-sensitive CRC cells. Last, JQ1+Bortezomib inhibited tumor growth and angiogenesis in CRC cell line xenograft model and four PDX models. Our results indicate that anti-angiogenic effect of JQ1 plays a vital role in therapeutic effect of JQ1 in CRC, and provide a rationale for combined inhibition of BET proteins and NF-κB as a potential therapy for CRC. |
| تدمد: | 2041-4889 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::98dfba00770d13875803bd1ad3fe0c09Test https://doi.org/10.1038/s41419-018-0354-yTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....98dfba00770d13875803bd1ad3fe0c09 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20414889 |
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