Yao Weilong, Yue Ping, Khuri Fadlo R, Sun Shi-Yong
Department of Respiration, Xiangya Hospital and Xiangya School of Medicine, Central South University, Changsha, Hunan, PR China.
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
Oncotarget. 2015 Oct 27;6(33):34669-79. doi: 10.18632/oncotarget.5785.
Inhibition of BET bromodomains (BRDs) has emerged as a promising cancer therapeutic strategy. Accordingly, inhibitors of BRDs such as JQ1 have been actively developed and some have reached clinical testing. However, the mechanisms by which this group of inhibitors exerts their anticancer activity, including induction of apoptosis, have not been fully elucidated. This report reveals a previously uncovered activity of JQ1 in inducing c-FLIP degradation and enhancing TRAIL-induced apoptosis. JQ1 potently decreased c-FLIP (both long and short forms) levels in multiple cancer cell lines without apparently increasing the expression of DR5 and DR4. Consequently, JQ1, when combined with TRAIL, synergistically induced apoptosis; this enhanced apoptosis-inducing activity could be abolished by enforced expression of ectopic FLIPL or FLIPS. Hence it appears that JQ1 decreases c-FLIP levels, resulting in enhancement of TRAIL-induced apoptosis. Inhibition of proteasome with MG132 prevented JQ1-induced c-FLIP reduction. Moreover, JQ1 decreased c-FLIP stability. Therefore, JQ1 apparently decreases c-FLIP levels through facilitating its proteasomal degradation. Genetic inhibition of either BRD4 or c-Myc by knocking down their expression failed to mimic JQ1 in decreasing c-FLIP and enhancing TRAIL-induced apoptosis, suggesting that JQ1 induces c-FLIP degradation and enhances TRAIL-induced apoptosis independent of BRD4 or c-Myc inhibition. In summary, our findings in this study highlights a novel biological function of JQ1 in modulating apoptosis and warrant further study of the potential treatment of cancer with the JQ1 and TRAIL combination.
抑制BET溴结构域（BRD）已成为一种有前景的癌症治疗策略。因此，像JQ1这样的BRD抑制剂已被积极研发，并且一些已进入临床试验阶段。然而，这类抑制剂发挥其抗癌活性的机制，包括诱导细胞凋亡，尚未完全阐明。本报告揭示了JQ1在诱导c-FLIP降解和增强TRAIL诱导的细胞凋亡方面一种先前未被发现的活性。JQ1能有效降低多种癌细胞系中c-FLIP（长、短两种形式）的水平，而未明显增加DR5和DR4的表达。因此，JQ1与TRAIL联合使用时，能协同诱导细胞凋亡；这种增强的凋亡诱导活性可通过强制表达异位的FLIPL或FLIPS而被消除。所以看起来JQ1降低了c-FLIP水平，导致TRAIL诱导的细胞凋亡增强。用MG132抑制蛋白酶体可阻止JQ1诱导的c-FLIP减少。此外，JQ1降低了c-FLIP的稳定性。因此，JQ1显然是通过促进其蛋白酶体降解来降低c-FLIP水平的。通过敲低BRD4或c-Myc的表达对其进行基因抑制，在降低c-FLIP和增强TRAIL诱导的细胞凋亡方面未能模拟JQ1的作用，这表明JQ1诱导c-FLIP降解和增强TRAIL诱导的细胞凋亡与抑制BRD4或c-Myc无关。总之，我们在本研究中的发现突出了JQ1在调节细胞凋亡方面的一种新的生物学功能，并为进一步研究JQ1与TRAIL联合治疗癌症的潜力提供了依据。
