Dysregulation of DNA epigenetic modulators during prostate carcinogenesis in an eastern Indian patient population: Prognostic implications

The role of epigenetic alteration in prostate cancer pathogenesis was reported. We aimed to analyze dysregulation of DNA methylase (DNA methyl transferase/DNMT) and demethylase (ten eleven translocase/TET) and the associated interplay between them during prostate tumorigenesis. Promoter methylation...

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Published in:Pathology, research and practice research and practice, 2024-01, Vol.253, p.154970-154970, Article 154970
Main Authors: Banerjee, Anwesha, Bardhan, Abhishek, Sarkar, Purandar, Datta, Chhanda, Pal, Dilip Kumar, Saha, Abhik, Ghosh, Amlan
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Language:English
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5hmC
Bone metastasis
DNMT
Epigenetic alteration
Prostate cancer
TET
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container_title Pathology, research and practice
container_volume 253
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Bardhan, Abhishek
Sarkar, Purandar
Datta, Chhanda
Pal, Dilip Kumar
Saha, Abhik
Ghosh, Amlan
description The role of epigenetic alteration in prostate cancer pathogenesis was reported. We aimed to analyze dysregulation of DNA methylase (DNA methyl transferase/DNMT) and demethylase (ten eleven translocase/TET) and the associated interplay between them during prostate tumorigenesis. Promoter methylation and RNA/protein expression of selected DNMT and TETs were analysed in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Genomic 5-hydroxymethylcytosine (5hmC) level was detected and correlated with DNMT and TET proteins. Clinicopathological association of molecular data was done. Our data revealed a very low frequency of promoter methylation for DNMT1 (5-3% and high frequency for TET1 (22–38%), TET2 (68–90 %), and TET3 (43-32 %) in BPH and PCa. The promoter methylation of DNMT1 (p = 0.019) showed a significantly decreasing trend, while that of TET1 (p = 0.0005) and TET2 (p 
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We aimed to analyze dysregulation of DNA methylase (DNA methyl transferase/DNMT) and demethylase (ten eleven translocase/TET) and the associated interplay between them during prostate tumorigenesis. Promoter methylation and RNA/protein expression of selected DNMT and TETs were analysed in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Genomic 5-hydroxymethylcytosine (5hmC) level was detected and correlated with DNMT and TET proteins. Clinicopathological association of molecular data was done. Our data revealed a very low frequency of promoter methylation for DNMT1 (5-3% and high frequency for TET1 (22–38%), TET2 (68–90 %), and TET3 (43-32 %) in BPH and PCa. The promoter methylation of DNMT1 (p = 0.019) showed a significantly decreasing trend, while that of TET1 (p = 0.0005) and TET2 (p &lt; 0.0001) showed an increasing trend from normal prostate to BPH to PCa, indicating their epigenetic dysregulation during prostate tumorigenesis. RNA/protein overexpression of DNMT1 and reduced expression of TET1 and TET2 in PCa compared to BPH were associated with the promoter methylation status of genes. The 5hmC level was significantly lower in PCa than in BPH and correlated negatively with DNMT1 but positively with TET1 and TET2 proteins, suggesting dysregulation of DNA methylase and de-methylase activities during prostate tumorigenesis. Lastly, tumors having methylated TET1 and TET2 promoters showed advanced clinicopathological features (a higher PSA level/Gleason score) and increased risk of bone metastasis. In conclusion, DNMT1 upregulation and epigenetic silencing of TET1 and TET2 was seen during PCa development. TET1 and TET2 promoter methylation has prognostic importance. •DNMT1 over-expression and epigenetic silencing of TET1 and TET2 was seen in prostate tumorigenesis.•An association of DNMT1 protein was seen with promoter methylation of TET1 and TET2.•DNMT1, TET1 and TET2 were functionally correlated with depleted 5hmC level in prostate tumor.•TET1 and TET2 promoter methylation in tumor can jointly predict the incidence of bone metastasis.</description><identifier>ISSN: 0344-0338</identifier><identifier>EISSN: 1618-0631</identifier><identifier>DOI: 10.1016/j.prp.2023.154970</identifier><identifier>PMID: 38056136</identifier><language>eng</language><publisher>Germany: Elsevier GmbH</publisher><subject>5hmC ; Bone metastasis ; DNMT ; Epigenetic alteration ; Prostate cancer ; TET</subject><ispartof>Pathology, research and practice, 2024-01, Vol.253, p.154970-154970, Article 154970</ispartof><rights>2023 Elsevier GmbH</rights><rights>Copyright © 2023 Elsevier GmbH. 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We aimed to analyze dysregulation of DNA methylase (DNA methyl transferase/DNMT) and demethylase (ten eleven translocase/TET) and the associated interplay between them during prostate tumorigenesis. Promoter methylation and RNA/protein expression of selected DNMT and TETs were analysed in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Genomic 5-hydroxymethylcytosine (5hmC) level was detected and correlated with DNMT and TET proteins. Clinicopathological association of molecular data was done. Our data revealed a very low frequency of promoter methylation for DNMT1 (5-3% and high frequency for TET1 (22–38%), TET2 (68–90 %), and TET3 (43-32 %) in BPH and PCa. The promoter methylation of DNMT1 (p = 0.019) showed a significantly decreasing trend, while that of TET1 (p = 0.0005) and TET2 (p &lt; 0.0001) showed an increasing trend from normal prostate to BPH to PCa, indicating their epigenetic dysregulation during prostate tumorigenesis. RNA/protein overexpression of DNMT1 and reduced expression of TET1 and TET2 in PCa compared to BPH were associated with the promoter methylation status of genes. The 5hmC level was significantly lower in PCa than in BPH and correlated negatively with DNMT1 but positively with TET1 and TET2 proteins, suggesting dysregulation of DNA methylase and de-methylase activities during prostate tumorigenesis. Lastly, tumors having methylated TET1 and TET2 promoters showed advanced clinicopathological features (a higher PSA level/Gleason score) and increased risk of bone metastasis. In conclusion, DNMT1 upregulation and epigenetic silencing of TET1 and TET2 was seen during PCa development. 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We aimed to analyze dysregulation of DNA methylase (DNA methyl transferase/DNMT) and demethylase (ten eleven translocase/TET) and the associated interplay between them during prostate tumorigenesis. Promoter methylation and RNA/protein expression of selected DNMT and TETs were analysed in normal prostate, benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Genomic 5-hydroxymethylcytosine (5hmC) level was detected and correlated with DNMT and TET proteins. Clinicopathological association of molecular data was done. Our data revealed a very low frequency of promoter methylation for DNMT1 (5-3% and high frequency for TET1 (22–38%), TET2 (68–90 %), and TET3 (43-32 %) in BPH and PCa. The promoter methylation of DNMT1 (p = 0.019) showed a significantly decreasing trend, while that of TET1 (p = 0.0005) and TET2 (p &lt; 0.0001) showed an increasing trend from normal prostate to BPH to PCa, indicating their epigenetic dysregulation during prostate tumorigenesis. RNA/protein overexpression of DNMT1 and reduced expression of TET1 and TET2 in PCa compared to BPH were associated with the promoter methylation status of genes. The 5hmC level was significantly lower in PCa than in BPH and correlated negatively with DNMT1 but positively with TET1 and TET2 proteins, suggesting dysregulation of DNA methylase and de-methylase activities during prostate tumorigenesis. Lastly, tumors having methylated TET1 and TET2 promoters showed advanced clinicopathological features (a higher PSA level/Gleason score) and increased risk of bone metastasis. In conclusion, DNMT1 upregulation and epigenetic silencing of TET1 and TET2 was seen during PCa development. TET1 and TET2 promoter methylation has prognostic importance. •DNMT1 over-expression and epigenetic silencing of TET1 and TET2 was seen in prostate tumorigenesis.•An association of DNMT1 protein was seen with promoter methylation of TET1 and TET2.•DNMT1, TET1 and TET2 were functionally correlated with depleted 5hmC level in prostate tumor.•TET1 and TET2 promoter methylation in tumor can jointly predict the incidence of bone metastasis.</abstract><cop>Germany</cop><pub>Elsevier GmbH</pub><pmid>38056136</pmid><doi>10.1016/j.prp.2023.154970</doi><tpages>1</tpages></addata></record>
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subjects 5hmC
Bone metastasis
DNMT
Epigenetic alteration
Prostate cancer
TET
title Dysregulation of DNA epigenetic modulators during prostate carcinogenesis in an eastern Indian patient population: Prognostic implications
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