文章：

HDAC11活性有助于葡萄膜黑色素瘤中MEK抑制剂的逃逸

HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma 

原文发布日期：2022-03-24 

英文摘要：

We previously demonstrated that pan-HDAC inhibitors could limit escape from MEK inhibitor (MEKi) therapy in uveal melanoma (UM) through suppression of AKT and YAP/TAZ signaling. Here, we focused on the role of specific HDACs in therapy adaptation. Class 2 UM displayed higher expression of HDACs 1, 2, and 3 than Class 1, whereas HDACs 6, 8, and 11 were uniformly expressed. Treatment of UM cells with MEKi led to modulation of multiple HDACs, with the strongest increases observed in HDAC11. RNA-seq analysis showed MEKi to decrease the expression of multiple HDAC11 target genes. Silencing of HDAC11 significantly reduced protein deacetylation, enhanced the apoptotic response to MEKi and reduced growth in long-term colony formation assays across multiple UM cell lines. Knockdown of HDAC11 led to decreased expression of TAZ in some UM cell lines, accompanied by decreased YAP/TAZ transcriptional activity and reduced expression of multiple YAP/TAZ target genes. Further studies showed this decrease in TAZ expression to be associated with increased LKB1 activation and modulation of glycolysis. In an in vivo model of uveal melanoma, silencing of HDAC11 limited the escape to MEKi therapy, an effect associated with reduced levels of Ki67 staining and increased cleaved caspase-3. We have demonstrated a novel role for adaptive HDAC11 activity in UM cells, that in some cases modulates YAP/TAZ signaling leading to MEKi escape. 

摘要翻译： 

我们既往研究发现，泛组蛋白去乙酰化酶抑制剂（pan-HDAC inhibitors）可通过抑制AKT和YAP/TAZ信号通路，限制葡萄膜黑色素瘤（UM）对MEK抑制剂（MEKi）治疗的逃逸。本研究着重探讨特定HDAC亚型在治疗适应性中的作用。2类UM中HDAC1、2、3的表达水平高于1类，而HDAC6、8、11的表达则保持稳定。MEKi处理UM细胞后可调控多种HDAC表达，其中HDAC11的上调最为显著。RNA测序分析显示MEKi能降低多个HDAC11靶基因的表达。沉默HDAC11可显著降低蛋白质去乙酰化水平，增强MEKi诱导的细胞凋亡反应，并在多株UM细胞系的长期集落形成实验中抑制生长。在某些UM细胞系中，敲低HDAC11会导致TAZ表达下降，伴随YAP/TAZ转录活性降低及多个YAP/TAZ靶基因表达减少。进一步研究表明，TAZ表达下降与LKB1活化增强及糖酵解调控相关。在葡萄膜黑色素瘤体内模型中，沉默HDAC11可抑制MEKi治疗逃逸现象，该效应与Ki67染色减少和裂解caspase-3增加相关。本研究揭示了适应性HDAC11活性在UM细胞中的新功能，即在某些情况下通过调控YAP/TAZ信号通路介导MEKi治疗逃逸。

原文链接：

HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma