MAPK Inhibitors Enhance HDAC Inhibitor-Induced Redifferentiation in Papillary Thyroid Cancer Cells Harboring BRAFV600E : An In Vitro
MAPK Inhibitors Enhance HDAC Inhibitor-Induced Redifferentiation in Papillary Thyroid Cancer Cells Harboring BRAFV600E : An In Vitro
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MAPK 抑制剂增强 HDAC 抑制剂诱导的携带 BRAF(V600E) 的甲状腺乳头状癌细胞的再分化：体外研究
DOI：
10.1016/j.omto.2019.01.007
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发表时间：
2019-03-29
影响因子：
5.7
通讯作者：
Chen, Libo
中科院分区：
文献类型：
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作者：
Fu, Hao;Cheng, Lingxiao;Chen, Libo
组蛋白去乙酰化酶抑制剂（HDACi）再分化治疗致死性放射性碘难治性甲状腺乳头状癌（RR-PTC）的临床疗效亟待提高。鉴于组蛋白乙酰化受损是BRAF（V600 E）-促分裂原活化蛋白激酶（MAPK）诱导的甲状腺碘代谢基因异常沉默的机制，HDAC和MAPK的双重抑制可能产生更有利的效果。在这项研究中，我们用HDACi（帕比司他）和MAPK抑制剂（达拉非尼或司美替尼）单独或联合处理BRAF（V600 E）突变体（BCPAP和K1）和BRAF野生型（BHP 2-7）细胞，我们测试了碘和葡萄糖代谢基因的表达，放射性碘摄取和流出以及毒性。我们发现，帕比司他单独增加碘代谢基因表达，促进放射性碘摄取和毒性，并抑制所有细胞中的GLUT 1表达。然而，MAPKi（达拉非尼或司美替尼）仅在BRAF（V600 E）突变细胞中诱导这些效应。帕比司他和MAPKi（达拉非尼或司美替尼）的联合治疗通过进一步改善钠-碘同向转运体（NIS）启动子处组蛋白的乙酰化水平，显示出比单独帕比司他更稳健的BRAF（V600 E）依赖性再分化作用。总之，MAPK抑制剂增强HDACi诱导的携带BRAF（V600 E）的PTC细胞的再分化，这证实了动物和临床试验。
Clinical efficacy of redifferentiation therapy with histone deacetylase inhibitor (HDACi) for lethal radioiodine-refractory papillary thyroid cancer (RR-PTC) is urgently needed to be improved. Given that the impairment of histone acetylation is a mechanism in BRAF(V600E)-mitogen-activated protein kinase (MAPK)-induced aberrant silencing of thyroid iodine-metabolizing genes, dual inhibition of HDAC and MAPK may produce a more favorable effect. In this study, we treated BRAF(V600E)-mutant (BCPAP and K1) and BRAF-wild-type (BHP 2-7) cells with HDACi (panobinostat) and MAPK inhibitor (dabrafenib or selumetinib), alone or in combination, and we tested the expression of iodine- and glucose-metabolizing genes, radioiodine uptake and efflux, and toxicity. We found that panobinostat alone increased iodine-metabolizing gene expression, promoted radioiodine uptake and toxicity, and suppressed GLUT1 expression in all the cells. However, MAPKi (dabrafenib or selumetinib) induced these effects only in BRAF(V600E)-mutant cells. Combined treatment with panobinostat and MAPKi (dabrafenib or selumetinib) displayed a more robust BRAF(V600E)-dependent redifferentiation effect than panobinostat alone via further improving the acetylation level of histone at the sodium-iodide symporter (NIS) promoter. In conclusion, MAPK inhibitors enhance HDACi-induced redifferentiation in PTC cells harboring BRAF(V600E), warranting animal and clinical trials.