The new 6q27 tumor suppressor DACT2, frequently silenced by CpG methylation, sensitizes nasopharyngeal cancer cells to paclitaxel and 5-FU toxicity via β-catenin/Cdc25c signaling and G2/M arrest.
The new 6q27 tumor suppressor DACT2, frequently silenced by CpG methylation, sensitizes nasopharyngeal cancer cells to paclitaxel and 5-FU toxicity via β-catenin/Cdc25c signaling and G2/M arrest.
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DOI：
10.1186/s13148-018-0459-2
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发表时间：
2018-02-27
影响因子：
5.7
通讯作者：
Xiang T
中科院分区：
文献类型：
--
作者：
Zhang Y;Fan J;Fan Y;Li L;He X;Xiang Q;Mu J;Zhou D;Sun X;Yang Y;Ren G;Tao Q;Xiang T
鼻咽癌是包括香港和东南亚在内的南方中国地区的高发肿瘤，常与EB病毒感染相关。EB病毒的表观遗传学在鼻咽癌的发病中起着关键作用。通过前期的CpG甲基组研究，我们确定蓬乱的β-连环蛋白2结合拮抗剂(DACT2)是鼻咽癌的甲基化靶标。虽然DACT2被证明在一些肿瘤中调节Wnt信号，但它在鼻咽癌发病中的作用尚不清楚。采用RT-PCR、qPCR、MSP和BGS等方法检测鼻咽癌组织中DACT2基因的表达水平和启动子甲基化情况。用Transwell、流式细胞仪、集落形成和BrdU-ELISA法检测DACT2对不同生物学功能的影响。采用免疫荧光、Western印迹和双荧光素酶报告分析等方法探讨DACT2的作用机制。用药敏试验检测DACT2对化疗药物的影响。我们发现DACT2很容易在包括上呼吸道组织在内的多种正常成人组织中表达。然而，它在鼻咽癌中经常下调，并与启动子甲基化相关。DNA甲基转移酶抑制剂5-氮杂-2‘-脱氧胞苷恢复其在鼻咽癌细胞中的表达。在29/32(91%)的鼻咽癌组织中进一步检测到DACT2甲基化，而在任何(0/8)正常鼻咽组织中未检测到DACT2甲基化。在鼻咽癌细胞中异位表达DACT2通过下调基质金属蛋白酶抑制鼻咽癌细胞的增殖、迁移和侵袭，并通过直接抑制β-catenin/CDc25c信号通路诱导鼻咽癌细胞G2/M期停滞，从而使鼻咽癌细胞对紫杉醇和5-FU增敏，而不是顺铂。我们的结果表明，在鼻咽癌中，DACT2经常通过CpG甲基化而表观失活，而它通过抑制β-catenin/CDc25c信号来抑制鼻咽癌细胞的增殖和转移。我们的研究提示DACT2启动子甲基化是一种潜在的鼻咽癌检测和化疗指导的表观遗传学标志物。
Nasopharyngeal carcinoma (NPC) is prevalent in South China, including Hong Kong and Southeast Asia, constantly associated with Epstein-Barr virus (EBV) infection. Epigenetic etiology attributed to EBV plays a critical role in NPC pathogenesis. Through previous CpG methylome study, we identified Disheveled-associated binding antagonist of beta-catenin 2 (DACT2) as a methylated target in NPC. Although DACT2 was shown to regulate Wnt signaling in some carcinomas, its functions in NPC pathogenesis remain unclear. RT-PCR, qPCR, MSP, and BGS were applied to measure expression levels and promoter methylation of DACT2 in NPC. Transwell, flow cytometric analysis, colony formation, and BrdU-ELISA assay were used to assess different biological functions affected by DACT2. Immunofluorescence, Western blot, and dual-luciferase reporter assay were used to explore the mechanisms of DACT2 functions. Chemosensitivity assay was used to measure the impact of DACT2 on chemotherapy drugs. We found that DACT2 is readily expressed in multiple normal adult tissues including upper respiratory tissues. However, it is frequently downregulated in NPC and correlated with promoter methylation. DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine restored its expression in NPC cells. DACT2 methylation was further detected in 29/32 (91%) NPC tumors but not in any (0/8) normal nasopharyngeal tissue samples. Ectopic expression of DACT2 in NPC cells suppressed their proliferation, migration, and invasion through downregulating matrix metalloproteinases. DACT2 expression also induced G2/M arrest in NPC cells through directly suppressing β-catenin/Cdc25c signaling, which sensitized NPC cells to paclitaxel and 5-FU, but not cisplatin. Our results demonstrate that DACT2 is frequently inactivated epigenetically by CpG methylation in NPC, while it inhibits NPC cell proliferation and metastasis via suppressing β-catenin/Cdc25c signaling. Our study suggests that DACT2 promoter methylation is a potential epigenetic biomarker for the detection and chemotherapy guidance of NPC.
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影响因子：
7.3
作者：
Jia, Yan;Yang, Yunsheng;Brock, Malcolm V.;Zhan, Qimin;Herman, James G.;Guo, Mingzhou
通讯作者：
Guo, Mingzhou
影响因子：
11.8
作者：
Cheyette, BNR;Waxman, JS;Moon, RT
通讯作者：
Moon, RT
影响因子：
2.4
作者：
He, Dan;Zeng, Quan;Hu, Guohua
通讯作者：
Hu, Guohua
影响因子：
4.8
作者：
Su, Ying;Zhang, Long;Chen, Ye-Guang
通讯作者：
Chen, Ye-Guang
影响因子：
3.7
作者：
Husseiny MI;Kuroda A;Kaye AN;Nair I;Kandeel F;Ferreri K
通讯作者：
Ferreri K