Epigenetic therapy of cancer stem and progenitor cells by targeting DNA methylation machineries

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, DNMT3Aand 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". 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.Wongtrakoongate P. Epigenetic therapy of cancer stem and REVIEWSubmit a

Parent-of-origin effects of A1CF and AGO2 on testicular germ-cell tumors, testicular abnormalities, and fertilization bias

“…Aberrant DNA methylation is associated with familial TGCT susceptibility in humans (33,108). DNA methyltransferases (DNMTs) are known to be essential for the progression and aggressiveness of tumors such as TGCTs (109)(110)(111). In our filial TGCT cases, paternal TGCTs might express factors that indirectly alter the methylation pattern at the promotors of TEs, miRNAs, and siRNAs (33,112,113), inherited elements that are direct targets of TGCT modifiers such as AGO2, DND1, and APOBEC1 (58,60,107).…”

Kaempferol Modulates DNA Methylation and Downregulates DNMT3B in Bladder Cancer

“…The DNA methylation is mostly relied on the expression of DNMTs. DNMT3A and DNMT3B are mostly associated with de novo DNA methylation, whereas DNMT1 is associated with maintaining the DNA methylation patterns of genes [34, 35]. The spectrum of target sequences for DNMT3A and DNMT3B are different [36], therefore, selective inactivation of DNMT3A or DNMT3B may result in different DNA methylation.…”

Imprints and DPPA3 are bypassed during pluripotency- and differentiation-coupled methylation reprogramming in testicular germ cell tumors

“…The strong coexpression of DNMT3B and mCpH-pluri in both ECs and benign pluripotent states further supports the model whereby mCpHpluri is established de novo, and then upon differentiation to YST and TE, its maintenance is neglected by the more CpG-philic DNMT1 maintenance methyltransferase (Sperger et al 2003;Almstrup et al 2005;Biermann et al 2007;Chedin 2011;Tiedemann et al 2014). This may be relevant for subtype-targeted treatment because elevated DNMT3B expression in ECs has been linked to exquisite sensitivity to demethylating agents (Beyrouthy et al 2009;Biswal et al 2012;Wongtrakoongate 2015). Interestingly, DNMT3A would conceivably be capable of methyl-CpH in ECs; yet, as this methyltransferase plays a specialized role in neurons and germ cell methylation, including gDMR de novo paternalization in the latter (Chedin 2011), the greater prominence of DNMT3B in ECs, coupled with mCpH-pluri, further distances the early developmental origin of TGCTs from germ cells downstream from de novo imprint paternalization.…”