HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma.
HDAC11 activity contributes to MEK inhibitor escape in uveal melanoma.
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DOI：
10.1038/s41417-022-00452-7
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发表时间：
2022-12
影响因子：
6.4
通讯作者：
Smalley, Keiran S. M.
中科院分区：
文献类型：
--
作者：
Sriramareddy, Sathya Neelature;Faiao-Flores, Fernanda;Emmons, Michael F.;Saha, Biswarup;Chellappan, Srikumar;Wyatt, Clayton;Smalley, Inna;Licht, Jonathan D.;Durante, Michael A.;Harbour, J. William;Smalley, Keiran S. M.
我们先前证明，泛HDAC抑制剂可以通过抑制AKT和雅普/TAZ信号传导来限制葡萄膜黑色素瘤（UM）中MEK抑制剂（MEKi）治疗的逃逸。在这里，我们专注于特定HDAC在治疗适应中的作用。2类UM显示HDAC 1、2和3的表达高于1类，而HDAC 6、8和11均匀表达。用MEKi处理UM细胞导致多种HDAC的调节，其中在HDAC 11中观察到最强的增加。RNA-seq分析显示MEKi降低多个HDAC 11靶基因的表达。HDAC 11的沉默显著降低了蛋白质脱乙酰化，增强了对MEKi的凋亡反应，并在多种UM细胞系的长期集落形成测定中降低了生长。HDAC 11的敲低导致在一些UM细胞系中TAZ的表达降低，伴随着雅普/TAZ转录活性降低和多个雅普/TAZ靶基因的表达降低。进一步的研究表明，TAZ表达的减少与LKB 1激活的增加和糖酵解的调节有关。在葡萄膜黑色素瘤的体内模型中，HDAC 11的沉默限制了对MEKi治疗的逃避，这一效应与Ki 67染色水平降低和裂解的半胱天冬酶-3增加相关。我们已经证明了适应性HDAC 11活性在UM细胞中的新作用，在某些情况下调节雅普/TAZ信号传导，导致MEKi逃逸。
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 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.
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DOI：
10.2217/14796694.4.5.629
发表时间：
2008-10
期刊：
Future oncology (London, England)
影响因子：
--
作者：
Landreville S;Agapova OA;Harbour JW
通讯作者：
Harbour JW
影响因子：
--
作者：
Faiao-Flores, Fernanda;Quincoces Suarez, Jose Agustin;Maria, Durvanei Augusto
通讯作者：
Maria, Durvanei Augusto
影响因子：
3.7
作者：
Field MG;Harbour JW
通讯作者：
Harbour JW
影响因子：
1
作者：
Levinzon, Louis;Madigan, Michele;Cherepanoff, Svetlana
通讯作者：
Cherepanoff, Svetlana
影响因子：
4.8
作者：
Gao, L;Cueto, MA;Atadja, P
通讯作者：
Atadja, P