Co-inhibition of BET proteins and NF-kappa B as a potential therapy for colorectal cancer through synergistic inhibiting MYC and FOXM1 expressions

作者：Wu Tingyu; Wang Guanghui; Chen Wei; Zhu Zhehui; Liu Yun; Huang Zhenyu; Huang Yuji; Du Peng; Yang Yili; Liu Chen Ying^*; Cui Long^*

来源：CELL DEATH & DISEASE, 2018, 9: 315.

DOI：10.1038/s41419-018-0354-y

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-kappa B 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-kappa B by Bortezomib or NF-kappa B 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-kappa B by I kappa Ba siRNA induced resistance to JQ1 in BET-isensitive 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-kappa B as a potential therapy for CRC.

• 单位
  中国医学科学院; 上海交通大学