Cellular and Molecular Research Center, Shahrekord University of Medical Sciences, PO Box: 88155-571, Shahrekord, Iran.
Department of Microbiology and Immunology, Shahrekord University of Medical Sciences, Shahrekord, Iran.
Mol Biol Rep. 2023 Oct;50(10):8319-8328. doi: 10.1007/s11033-023-08718-5. Epub 2023 Aug 17.
Bromodomain and extra-terminal (BET) proteins are recognized acetylated lysine of histone 4 and act as scaffolds to recruit many other proteins to promoters and enhancers of active genes, especially at the super-enhancers of key genes, driving the transcription process and have been identified as potential therapeutic targets in breast cancer. However, the efficacy of BET inhibitors such as JQ1 in breast cancer therapy is impeded by interleukin-6 (IL-6) through an as-yet-defined mechanism.
We investigated the interplay between IL-6 and JQ1 in MCF-7 and MDA-MB-231 human breast cancer cells. The results demonstrate that the efficacy of JQ1 on the inhibition of cell growth and apoptosis was stronger in MDA-MB-231 cells than in MCF-7 cells. Further, MCF-7 cells, but not MDA-MB-231 cells, exhibited increased expression of CXCR4 following IL-6 treatment. JQ1 significantly reduced CXCR4 surface expression in both cell lines and diminished the effects of IL-6 pre-treatment on MCF-7 cells. While IL-6 suppressed the extension of breast cancer stem cells in MCF-7 cells, JQ1 impeded its inhibitory effect. In MCF-7 cells JQ1 increased the number of senescent cells in a time-dependent manner.
Analysis of gene expression indicated that JQ1 and IL-6 synergistically increase SNAIL expression and decrease c-MYC expression in MCF-7 cells. So, the BET proteins are promising, novel therapeutic targets in late-stage breast cancers. BET inhibitors similar to JQ1 show promise as therapeutic candidates for breast cancers, especially when triple-negative breast cancer cells are increased and/or tumor-promoting factors like IL-6 exist in the tumor microenvironment.
溴结构域和末端结构域（BET）蛋白识别组蛋白 4 的乙酰化赖氨酸，并作为支架招募许多其他蛋白质到活性基因的启动子和增强子，特别是在关键基因的超级增强子上，驱动转录过程，并已被确定为乳腺癌的潜在治疗靶点。然而，BET 抑制剂（如 JQ1）在乳腺癌治疗中的疗效受到白细胞介素 6（IL-6）的阻碍，其机制尚不清楚。
我们研究了 IL-6 和 JQ1 在 MCF-7 和 MDA-MB-231 人乳腺癌细胞中的相互作用。结果表明，JQ1 抑制细胞生长和凋亡的效果在 MDA-MB-231 细胞中强于 MCF-7 细胞。此外，IL-6 处理后 MCF-7 细胞而非 MDA-MB-231 细胞表达的 CXCR4 增加。JQ1 显著降低了两种细胞系中 CXCR4 的表面表达，并减弱了 IL-6 预处理对 MCF-7 细胞的作用。虽然 IL-6 抑制了 MCF-7 细胞中乳腺癌干细胞的扩增，但 JQ1 阻碍了其抑制作用。在 MCF-7 细胞中，JQ1 呈时间依赖性地增加衰老细胞的数量。
基因表达分析表明，JQ1 和 IL-6 协同增加 MCF-7 细胞中 SNAIL 的表达并降低 c-MYC 的表达。因此，BET 蛋白是晚期乳腺癌有前途的新型治疗靶点。类似于 JQ1 的 BET 抑制剂有望成为乳腺癌的治疗候选药物，特别是当三阴性乳腺癌细胞增加和/或肿瘤促进因子如 IL-6 存在于肿瘤微环境中时。
