Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

Tian, Jing; Lee, Soo Ok; Liang, Liang; Luo, Jie; Huang, Chiung‐Kuei; Li, Lei; Niu, Yuanjie; Chang, Chawnshang

doi:10.1074/jbc.m112.395574

Cited by 58 publications

(51 citation statements)

References 59 publications

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“…Treatment of prostate cancer stem cells with Aza-dC led to an up-regulation of AR and a decrease in proliferation and tumor formation. Moreover, Aza-dC treatment also induced differentiation of the cancer stem cells, which is correlated with a reduced expression of stem cell-associated genes OCT4 and NANOG [92] . Thus, this study suggests that the inhibition of DNA methylation might be clinically translated for patients having prostate cancers with androgen-independent feature.…”

Section: Prostate Cancermentioning

confidence: 99%

“…The inhibitory role of AR in aggressiveness of prostate cancer is supported by loss of AR expression via promoter DNA methylation [88][89][90][91] . Interestingly, expression of AR is also reduced in prostate cancer stem cells particularly with high CD133 expression level [92] . Treatment of prostate cancer stem cells with Aza-dC led to an up-regulation of AR and a decrease in proliferation and tumor formation.…”

Section: Prostate Cancermentioning

confidence: 99%

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

Wongtrakoongate

2015

WJSC

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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

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Section: Prostate Cancermentioning

confidence: 99%

Section: Prostate Cancermentioning

confidence: 99%

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

Wongtrakoongate

2015

WJSC

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“…Tian et al (12) showed a link between AR gene methylation and prostate cancer progression. These authors found that AR gene methylation in promoter regions was likely related to prostate stem/progenitor cell stemness and differentiation.…”

Section: Epigenetic Modulation Of Ar Gene Expression In Prostate Cancmentioning

confidence: 99%

Epigenetic modulation of AR gene expression in prostate cancer DU145 cells with the combination of sodium butyrate and 5′-Aza-2′-deoxycytidine

et al. 2016

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Abstract. The androgen receptor (AR) plays an essential role in the development and progression of prostate cancer. Castration-resistant prostate cancer (CRPC) is a consequence of androgen deprivation therapy. Unchecked CRPC followed by metastasis is lethal. Some CRPCs show decreased AR gene expression due to epigenetic mechanisms such as DNA methylation and histone deacetylation. The aim of this study was to epigenetically modulate the methylated state of the AR gene leading to targeted demethylation and AR gene expression in androgen-independent human prostate cancer DU145 cell line, representing the CRPC model with very low or undetectable AR levels. The cell treatment was based on single and combined applications of two epigenetic inhibitors, sodium butyrate (NaB) as histone deacetylases inhibitor and 5'-Aza-2'-deoxycytidine (Aza-dC) as DNA methyltransferases inhibitor. We found that the Aza-dC in combination with NaB may help reduce the toxicity of higher NaB concentrations in cancer cells. In normal RWPE-1 cells and even stronger in cancer DU145 cells, the combined treatment induced both AR gene expression on the mRNA level and increased histone H4 acetylation in AR gene promoter. Also activation and maintenance of G2/M cell cycle arrest and better survival in normal RWPE-1 cells compared to cancer DU145 cells were observed after the treatments. These results imply the selective toxicity effect of both inhibitors used and their potentially more effective combined use in the epigenetic therapy of prostate cancer patients.

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“…29 In accord with these findings, 5-aza-29-deoxycytidine, which can effectively inhibit the methylation of the AR promoter, was reported to be an effective agent in the suppression of refractory progressions. 30 Changes in miRNA are also involved in the progression of CRPC.…”

Section: Mechanism Of Pca Progressionmentioning

confidence: 99%

Prostate cancer research in China

Ren¹,

Chen²,

Sun³

2013

Asian J Androl

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Prostate cancer (PCa) research in China has been on a rocketing trend in recent years. The first genome-wide association study (GWAS) in China identified two new PCa risk associated single nucleotide polymorphisms (SNPs). Next generation sequencing is beginning to be used, yielding novel findings: gene fusions, long non-coding RNAs and other variations. Mechanisms of PCa progression have been illustrated while various diagnosis biomarkers have been investigated extensively. Personalized therapy based on genetic factors, nano-medicine and traditional Chinese medicine has been the focus of experimental therapeutic research for PCa. This review intends to shed light upon the recent progress in PCa research in China and points out the possible breakthroughs in the future.

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Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

Cited by 58 publications

References 59 publications

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

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

Epigenetic modulation of AR gene expression in prostate cancer DU145 cells with the combination of sodium butyrate and 5′-Aza-2′-deoxycytidine

Prostate cancer research in China

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