Targeting DNA Methyltranferases in Urological Tumors

Marques-Magalhães, Ângela; Graça, Inês; Henrique, Rui; Jerónimo, Carmen

doi:10.3389/fphar.2018.00366

Cited by 34 publications

(42 citation statements)

References 298 publications

(344 reference statements)

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“…Despite positive responses in acute myeloid leukemia patients, acquired resistance is common, and these drugs are less effective in solid tumors. Improved versions are being developed and are in clinical trials for PCa (reviewed in [ 35 ] [ 36 ]), but this class of inhibitors will always have a global impact on the epigenome and therefore lack specificity for tumor suppressor genes. Thus, alternative methods targeting specific epigenetic alterations in cancer may be a more effective approach.…”

Section: Introductionmentioning

confidence: 99%

CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

Kardooni

González-Gualda

Stylianakis

et al. 2018

Cancers

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The DKK3 gene encodes a secreted protein, Dkk-3, that inhibits prostate tumor growth and metastasis. DKK3 is downregulated by promoter methylation in many types of cancer, including prostate cancer. Gene silencing studies have shown that Dkk-3 maintains normal prostate epithelial cell homeostasis by limiting TGF-β/Smad signaling. While ectopic expression of Dkk-3 leads to prostate cancer cell apoptosis, it is unclear if Dkk-3 has a physiological role in cancer cells. Here, we show that treatment of PC3 prostate cancer cells with the DNA methyltransferase (DNMT) inhibitor decitabine demethylates the DKK3 promoter, induces DKK3 expression, and inhibits TGF-β/Smad-dependent transcriptional activity. Direct induction of DKK3 expression using CRISPR-dCas9-VPR also inhibited TGF-β/Smad-dependent transcription and attenuated PC3 cell migration and proliferation. These effects were not observed in C4-2B cells, which do not respond to TGF-β. TGF-β signals can regulate gene expression directly via SMAD proteins and indirectly by increasing DNMT expression, leading to promoter methylation. Analysis of genes downregulated by promoter methylation and predicted to be regulated by TGF-β found that DKK3 induction increased expression of PTGS2, which encodes cyclooxygenase-2. Together, these observations provide support for using CRISPR-mediated induction of DKK3 as a potential therapeutic approach for prostate cancer and highlight complexities in Dkk-3 regulation of TGF-β signaling.

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Section: Introductionmentioning

confidence: 99%

CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

Kardooni

González-Gualda

Stylianakis

et al. 2018

Cancers

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“…Indeed, 5-azacytidine (or azacytidine (5-aza, Vidaza ® )) and 5-aza-2′-deoxycytidine (or decitabine (DAC, Dacogen ® )) are two DNMT inhibitors approved by the European Medicines Agency (EMA) and Food and Drug Administration (FDA) for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome, and chronic myelomonocytic leukemia (CMML) [ 30 , 57 , 58 ]. DNMT inhibitors can be classified, depending on their mechanism of action, as nucleoside and non-nucleoside analogues [ 24 ].…”

Section: Dnmt Inhibitorsmentioning

confidence: 99%

“…Specifically, a high mutation rate was found in KMT2D (also known as MLL2 ) gene and in KDM6A (also referred as UTX ), which encode a histone H3 lysine 4 methyltransferase and a histone lysine demethylase, respectively [ 21 , 22 , 23 ]. The most explored epigenetic mechanism is DNA methylation [ 18 , 24 ]. By comparing methylation patterns, Wolff et al found global hypomethylation in NMIBC, whereas hypermethylation patters were more commonly found in invasive tumors, supporting the concept that DNA methylation has an important role in BC development and aggressiveness, constituting a putative target for anti-cancer therapy [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

“…The most explored epigenetic mechanism is DNA methylation [ 18 , 24 ]. By comparing methylation patterns, Wolff et al found global hypomethylation in NMIBC, whereas hypermethylation patters were more commonly found in invasive tumors, supporting the concept that DNA methylation has an important role in BC development and aggressiveness, constituting a putative target for anti-cancer therapy [ 24 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

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DNA Methylation as a Therapeutic Target for Bladder Cancer

Nunes

Henrique

Jerónimo

et al. 2020

Cells

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Bladder cancer (BC) is the tenth most frequent cancer worldwide and is associated with high mortality when diagnosed in its most aggressive form, which is not reverted by the current treatment options. Thus, the development of new therapeutic strategies, either alternative or complementary to the current ones, is of major importance. The disruption of normal epigenetic mechanisms, namely, DNA methylation, is a known early event in cancer development. Consequently, DNA methyltransferase (DNMT) inhibitors constitute a promising therapeutic target for the treatment of BC. Although these inhibitors, mainly nucleoside analogues such as 5-azacytidine (5-aza) and decitabine (DAC), cause re-expression of tumor suppressor genes, inhibition of tumor cell growth, and increased apoptosis in BC experimental models and clinical trials, they also show important drawbacks that prevent their use as a valuable option for the treatment of BC. However, their combination with chemotherapy and/or immune-checkpoint inhibitors could aid in their implementation in the clinical practice. Here, we provide a comprehensive review of the studies exploring the effects of DNA methylation inhibition using DNMTs inhibitors in BC, from in vitro and in vivo studies to clinical trials.

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“…In terms of the DNA methylation status of different TGCT types, seminoma cases have very low DNA methylation levels, whereas nonseminomatous teratomas, yolk sac tumors, and choriocarcinomas show hypermethylation due to overexpression of DNA methyltransferases (DNMT) (4). In studies to clarify epigenetic mechanisms in TGCTs, promoter methylation was shown in genes such as tumor suppressors APC, ARF, TP53, RARB2, BRCA1, RASSF1A, cell cycle regulator CCNA1, DNA repair genes such as MGMT and hMLH1, transcription factor HOXA9, and PRSS21, which encodes the protein testisin in testis cell maturation (30). Although TGCT is generally curable, resistance to cisplatin is observed in a considerable proportion of patients.…”

Section: Genetic and Epigenetic Anomalies In Tgct Development And Thementioning

confidence: 99%

Genomic Evaluation of Testicular Germ Cell Tumors and its Role in Treatment Planning

Kılıçcıoğlu¹,

Konac²,

Sözen³

2018

uob

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The incidence of testicular germ cell tumors (TGCT) has significantly increased over the last 40 years and continues to increase among the young male population. The geographical differences show that a combination of genetic and environmental factors play a role in the pathogenesis of TGCT. However, since the actual mechanisms involved in the development of this disease have still not been fully explained, studies at the genomic level have gained importance. Although TGCTs respond well to chemotherapy, 20-30% of patients display classical chemotherapy resistance. There exists a need for detailed investigation of the molecular mechanisms responsible for such resistance. In this review, we briefly discussed the current information on some risk factors and genomic factors involved in the development of TGCTs.

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Targeting DNA Methyltranferases in Urological Tumors

Cited by 34 publications

References 298 publications

CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

CRISPR-Mediated Reactivation of DKK3 Expression Attenuates TGF-β Signaling in Prostate Cancer

DNA Methylation as a Therapeutic Target for Bladder Cancer

Genomic Evaluation of Testicular Germ Cell Tumors and its Role in Treatment Planning

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