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Front. Endocrinol. | doi: 10.3389/fendo.2019.00734

Resveratrol Reverses Retinoic Acid Resistance of Anaplastic Thyroid Cancer Cells via Demathylating CRABP2 Gene

Xin Liu1, Hong Li1, Mo-Li Wu1, Jiao Wu1, Yuan Sun1, Kai-Li Zhang1* and  Jia Liu1, 2*
  • 1Dalian Medical University, China
  • 2South China University of Technology, China

Abstract:

Background: Cellular retinoic acid binding protein 2 (CRABP2) mediates retinoic acid/RA anti-cancer pathway. Resveratrol effectively reverses RA tolerance and up-regulates CRABP2 expression of anaplastic thyroid cancer cell line THJ-11T. Because DNA methylation is responsible for CRABP2 silencing, CRABP2 methylation status of THJ-11T cells and demethylating effect of resveratrol on this gene are elucidated.

Materials and methods: The statuses of CRABP2 expression and methylation and the levels of DNA methyltransferases(DNMTs) DNMT1, DNMT3A, and DNMT3B of THJ-11T cells were examined before and after resveratrol treatment via multiple experimental methods. Human medulloblastoma UW228-2 cell line was cited as the positive control of CRABP2 methylation and gemcitabine as the demethylator control.

Results: RT-PCR, immunocytochemical staining and Western blotting showed that resveratrol significantly increased CRABP2 expression and RA sensitivity of THJ-11T and UW228-2 cells. Bisulfite sequencing showed 5 CpG methylation sites at CRABP2 promoter region of both cell lines, which were partially (3/5) demethylated by resveratrol and totally (5/5) by gemcitabine. DNMT1, DNMT3A, and DNMT3B were reduced in UW228-2 cells and DNMT1 and DNMT3A were reduced in THJ-11T cells after resveratrol treament in time-related fashion.

Conclusion: Resveratrol is able to erase CRABP2 methylation and thereby increased RA sensitivity of THJ-11T and UW228-2 cells. This study demonstrates the additional value of the natural polyphenolic compound resveratrol as a demethylator in cancer treatments.

Keywords: anaplastic thyroid cancer, DNA methyltransferase, CRABP2, DNA Methylation, Retinoic acid, resveratrol

Received: 25 Apr 2019; Accepted: 10 Oct 2019.

Copyright: © 2019 Liu, Li, Wu, Wu, Sun, Zhang and Liu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. Kai-Li Zhang, Dalian Medical University, Dalian, China, 18940993315@163.com
Mx. Jia Liu, Dalian Medical University, Dalian, China, jialiudl@dmu.edu.cn