Cargando…

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

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 ide...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Yan, Fan, Jiangxia, Fan, Yichao, Li, Lili, He, Xiaoqian, Xiang, Qin, Mu, Junhao, Zhou, Danfeng, Sun, Xuejuan, Yang, Yucheng, Ren, Guosheng, Tao, Qian, Xiang, Tingxiu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136178/
https://www.ncbi.nlm.nih.gov/pubmed/30359298
http://dx.doi.org/10.1186/s13148-018-0459-2
_version_ 1783354947427893248
author Zhang, Yan
Fan, Jiangxia
Fan, Yichao
Li, Lili
He, Xiaoqian
Xiang, Qin
Mu, Junhao
Zhou, Danfeng
Sun, Xuejuan
Yang, Yucheng
Ren, Guosheng
Tao, Qian
Xiang, Tingxiu
author_facet Zhang, Yan
Fan, Jiangxia
Fan, Yichao
Li, Lili
He, Xiaoqian
Xiang, Qin
Mu, Junhao
Zhou, Danfeng
Sun, Xuejuan
Yang, Yucheng
Ren, Guosheng
Tao, Qian
Xiang, Tingxiu
author_sort Zhang, Yan
collection PubMed
description 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.
format Online
Article
Text
id pubmed-6136178
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-61361782018-09-15 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 Zhang, Yan Fan, Jiangxia Fan, Yichao Li, Lili He, Xiaoqian Xiang, Qin Mu, Junhao Zhou, Danfeng Sun, Xuejuan Yang, Yucheng Ren, Guosheng Tao, Qian Xiang, Tingxiu Clin Epigenetics Research 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. BioMed Central 2018-02-27 /pmc/articles/PMC6136178/ /pubmed/30359298 http://dx.doi.org/10.1186/s13148-018-0459-2 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Zhang, Yan
Fan, Jiangxia
Fan, Yichao
Li, Lili
He, Xiaoqian
Xiang, Qin
Mu, Junhao
Zhou, Danfeng
Sun, Xuejuan
Yang, Yucheng
Ren, Guosheng
Tao, Qian
Xiang, Tingxiu
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136178/
https://www.ncbi.nlm.nih.gov/pubmed/30359298
http://dx.doi.org/10.1186/s13148-018-0459-2
work_keys_str_mv AT zhangyan thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT fanjiangxia thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT fanyichao thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT lilili thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT hexiaoqian thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT xiangqin thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT mujunhao thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT zhoudanfeng thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT sunxuejuan thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT yangyucheng thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT renguosheng thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT taoqian thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT xiangtingxiu thenew6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT zhangyan new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT fanjiangxia new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT fanyichao new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT lilili new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT hexiaoqian new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT xiangqin new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT mujunhao new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT zhoudanfeng new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT sunxuejuan new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT yangyucheng new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT renguosheng new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT taoqian new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest
AT xiangtingxiu new6q27tumorsuppressordact2frequentlysilencedbycpgmethylationsensitizesnasopharyngealcancercellstopaclitaxeland5futoxicityviabcatenincdc25csignalingandg2marrest