Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Jan 26, 2015; 7(1): 137-148
Published online Jan 26, 2015. doi: 10.4252/wjsc.v7.i1.137
Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries
Patompon Wongtrakoongate
Patompon Wongtrakoongate, Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
Author contributions: Wongtrakoongate P solely contributed to the manuscript
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Patompon Wongtrakoongate, PhD, Department of Biochemistry, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400, Thailand. p.wongtrakoongate@gmail.com
Telephone: +66-988-250113 Fax: +66-224-80375
Received: July 28, 2014
Peer-review started: July 28, 2014
First decision: September 16, 2014
Revised: October 14, 2014
Accepted: October 28, 2014
Article in press: December 16, 2014
Published online: January 26, 2015
Abstract

Recent advances in stem cell biology have shed light on how normal stem and progenitor cells can evolve to acquire malignant characteristics during tumorigenesis. The cancer counterparts of normal stem and progenitor cells might be occurred through alterations of stem cell fates including an increase in self-renewal capability and a decrease in differentiation and/or apoptosis. This oncogenic evolution of cancer stem and progenitor cells, which often associates with aggressive phenotypes of the tumorigenic cells, is controlled in part by dysregulated epigenetic mechanisms including aberrant DNA methylation leading to abnormal epigenetic memory. Epigenetic therapy by targeting DNA methyltransferases (DNMT) 1, DNMT3A and DNMT3B via 5-Azacytidine (Aza) and 5-Aza-2’-deoxycytidine (Aza-dC) has proved to be successful toward treatment of hematologic neoplasms especially for patients with myelodysplastic syndrome. In this review, I summarize the current knowledge of mechanisms underlying the inhibition of DNA methylation by Aza and Aza-dC, and of their apoptotic- and differentiation-inducing effects on cancer stem and progenitor cells in leukemia, medulloblastoma, glioblastoma, neuroblastoma, prostate cancer, pancreatic cancer and testicular germ cell tumors. Since cancer stem and progenitor cells are implicated in cancer aggressiveness such as tumor formation, progression, metastasis and recurrence, I propose that effective therapeutic strategies might be achieved through eradication of cancer stem and progenitor cells by targeting the DNA methylation machineries to interfere their “malignant memory”.

Keywords: Cancer stem and progenitor cells, DNA methylation, Epigenetic therapy, Aza-cytidine, Aza-deoxycytidine

Core tip: Several types of cancers can be developed from genetic and/or epigenetic instabilities of stem and progenitor cells. Epigenetic abnormality involving dysregulation of DNA methylation has been reported to implicate in cancer aggressiveness. Inhibition of DNA methyltransferase activity by DNA methylation inhibitors has shown promising results toward treatment of myelodysplastic syndrome, a disease associated with leukemic stem cells. This review summarizes evidences which are pertinent to the antitumorigenic potential of DNA methylation inhibitors 5-Azacytidine and 5-Aza-2’-deoxycytidine on cancer stem and progenitor cells including those of leukemia and other solid tumors.