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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摘要Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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
出版社接受日期14.02.2018
著者Zhang Y, Fan J, Fan Y, Li L, He X, Xiang Q, Mu J, Zhou D, Sun X, Yang Y, Ren GS, Tao Q, Xiang T
期刊名稱Clinical Epigenetics
出版年份2018
月份2
日期27
卷號10
出版社BMC (part of Springer Nature) / BioMed Central
文章號碼26
國際標準期刊號1868-7075
語言美式英語
關鍵詞DACT2, Nasopharyngeal cancer, Cdc25c, Paclitaxel, 5-FU

上次更新時間 2020-02-12 於 01:46