CDK9 inhibitors selectively target estrogen receptor-positive breast cancer cells through combined inhibition of MYB and MCL-1 expression.
CDK9 inhibitors selectively target estrogen receptor-positive breast cancer cells through combined inhibition of MYB and MCL-1 expression.
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DOI：
10.18632/oncotarget.6997
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发表时间：
2016-02-23
期刊：
影响因子：
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通讯作者：
Gonda TJ
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文献类型：
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作者：
Mitra P;Yang RM;Sutton J;Ramsay RG;Gonda TJ
我们之前的研究表明，MYB 是雌激素受体阳性 (ER+ve) 乳腺癌细胞增殖所必需的，并为其提供抗凋亡保护，而雌激素受体阳性 (ER+ve) 乳腺癌细胞几乎总是 MYB+ve。我们还表明，ER+ve 乳腺癌细胞中的 MYB 表达在转录延伸水平上受到调节，因此被 CDK9i 抑制。在这里，我们研究了 CDK9i 对乳腺癌细胞的影响以及 MYB 在这些影响中的参与。 ER+ve 乳腺癌细胞系（包括 MCF-7）对 CDK9i 的杀伤作用比 ER−ve/MYB−ve 细胞更敏感（> 10 倍）。此外，存活的细胞在细胞周期的 G2/M 期表现出阻断。重要的是，异位 MYB 表达赋予对细胞凋亡诱导、细胞杀伤和 G2/M 累积的抵抗力。相关 MYB 靶基因（包括 BCL2 和 CCNB1）的表达被 CDK9 抑制所抑制，并且异位 MYB 表达也可逆转这种情况。然而，通过 MYB 敲低或通过 ABT-199 治疗单独抑制 BCL2 不足以显着诱导细胞凋亡。进一步的研究表明，细胞凋亡诱导还需要抑制 MCL-1（CDK9 抑制的一个有据可查的靶标），而 CDK9i 诱导的细胞凋亡最大水平可能还涉及 BCL2L1 表达的抑制。总而言之，这些数据表明，与 ER-ve 乳腺癌细胞相比，BCL2 的 MYB 调节是 ER+ve 乳腺癌细胞对 CDK9 抑制的敏感性更高的基础，并且这些化合物代表了 ER+ve 乳腺癌和可能其他 MYB 依赖性癌症的潜在治疗方法。
Our previous studies showed that MYB is required for proliferation of, and confers protection against apoptosis on, estrogen receptor-positive (ER+ve) breast cancer cells, which are almost invariably also MYB+ve. We have also shown that MYB expression in ER+ve breast cancer cells is regulated at the level of transcriptional elongation and as such, is suppressed by CDK9i. Here we examined the effects of CDK9i on breast cancer cells and the involvement of MYB in these effects. ER+ve breast cancer cell lines including MCF-7 were much more sensitive (> 10 times) to killing by CDK9i than ER−ve/MYB−ve cells. Moreover, surviving cells showed a block at the G2/M phase of the cell cycle. Importantly, ectopic MYB expression conferred resistance to apoptosis induction, cell killing and G2/M accumulation. Expression of relevant MYB target genes including BCL2 and CCNB1 was suppressed by CDK9 inhibition, and this too was reversed by ectopic MYB expression. Nevertheless, inhibition of BCL2 alone either by MYB knockdown or by ABT-199 treatment was insufficient for significant induction of apoptosis. Further studies implied that suppression of MCL-1, a well-documented target of CDK9 inhibition, was additionally required for apoptosis induction, while maximal levels of apoptosis induced by CDK9i are likely to also involve inhibition of BCL2L1 expression. Taken together these data suggest that MYB regulation of BCL2 underlies the heightened sensitivity of ER+ve compared to ER−ve breast cancer cells to CDK9 inhibition, and that these compounds represent a potential therapeutic for ER+ve breast cancers and possibly other MYB-dependent cancers.