HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
HDAC1 and HDAC2 Double Knockout Triggers Cell Apoptosis in Advanced Thyroid Cancer
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DOI：
10.3390/ijms20020454
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发表时间：
2019-01-02
影响因子：
5.6
通讯作者：
Lee, Chia-Hwa
中科院分区：
文献类型：
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作者：
Lin, Ching-Ling;Tsai, Ming-Lin;Lee, Chia-Hwa
间变性甲状腺癌（ATC）和鳞状甲状腺癌（STC）均为罕见的晚期甲状腺恶性肿瘤，预后极差，平均中位生存时间为5个月，不到20%的患者在诊断后1年存活。ATC和STC的临床治疗非常相似，因为它们对放疗和化疗没有特别的反应。这激发了我们探索一种新的有效的临床批准的治疗ATC的方法。组蛋白去乙酰化酶抑制剂（HDACi）是近年来fda批准的治疗恶性肿瘤，特别是血液细胞癌的药物。因此，我们研究了HDACi药物是否作为晚期甲状腺癌的有效抗癌药物。panobinostat对SW579 STC细胞的IC50值为0.075 μ M。此外，panobinostat暴露激活组蛋白乙酰化，主要通过细胞周期阻滞和凋亡相关蛋白激活引发细胞死亡。利用CRISPR/Cas9敲除SW579细胞中的HDAC1和HDAC2基因，我们观察到组蛋白乙酰化水平和细胞周期阻滞得到增强，但对细胞生长没有影响。此外，与HDAC1和HDAC2单个KO细胞相比，HDAC1和HDAC2双敲除（KO）细胞表现出显著的细胞凋亡激活。这表明HDAC1和HDAC2在SW579细胞上存在表达和生物功能上的代偿。本研究为panobinostat在晚期甲状腺癌患者的临床应用提供了强有力的证据。
Anaplastic thyroid carcinoma (ATC) and squamous thyroid carcinoma (STC) are both rare and advanced thyroid malignancies with a very poor prognosis and an average median survival time of 5 months and less than 20% of affected patients are alive 1 year after diagnosis. The clinical management of both ATC and STC is very similar because they are not particularly responsive to radiotherapy and chemotherapy. This inspired us to explore a novel and effective clinically approved therapy for ATC treatment. Histone deacetylase inhibitor (HDACi) drugs are recently FDA-approved drug for malignancies, especially for blood cell cancers. Therefore, we investigated whether an HDACi drug acts as an effective anticancer drug for advanced thyroid cancers. Cell viability analysis of panobinostat treatment demonstrated a significant IC50 of 0.075 mu M on SW579 STC cells. In addition, panobinostat exposure activated histone acetylation and triggered cell death mainly through cell cycle arrest and apoptosis-related protein activation. Using CRISPR/Cas9 to knock out HDAC1 and HDAC2 genes in SW579 cells, we observed that the histone acetylation level and cell cycle arrest were enhanced without any impact on cell growth. Furthermore, HDAC1 and HDAC2 double knockout (KO) cells showed dramatic cell apoptosis activation compared to HDAC1 and HDAC2 individual KO cells. This suggests expressional and biofunctional compensation between HDAC1 and HDAC2 on SW579 cells. This study provides strong evidence that panobinostat can potentially be used in the clinic of advanced thyroid cancer patients.