Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes
Abstract Background Histones undergo extensive post-translational modifications and this epigenetic regulation plays an important role in modulating transcriptional programs capable of driving cancer progression. Acetylation of histone H3K18, associated with gene activation, is enhanced by P300 and...
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| Format: | Article |
| Language: | English |
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BMC
2017-12-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12885-017-3853-9 |
| _version_ | 1811216158061232128 |
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| author | Shivashankar Damodaran Nathan Damaschke Joseph Gawdzik Bing Yang Cedric Shi Glenn O. Allen Wei Huang John Denu David Jarrard |
| author_facet | Shivashankar Damodaran Nathan Damaschke Joseph Gawdzik Bing Yang Cedric Shi Glenn O. Allen Wei Huang John Denu David Jarrard |
| author_sort | Shivashankar Damodaran |
| collection | DOAJ |
| description | Abstract Background Histones undergo extensive post-translational modifications and this epigenetic regulation plays an important role in modulating transcriptional programs capable of driving cancer progression. Acetylation of histone H3K18, associated with gene activation, is enhanced by P300 and opposed by the deacetylase Sirtuin2 (SIRT2). As these enzymes represent an important target for cancer therapy, we sought to determine whether the underlying genes are altered during prostate cancer (PCa) progression. Methods Tissue microarrays generated from 71 radical prostatectomy patients were initially immunostained for H3K18Ac, P300 and SIRT2. Protein levels were quantified using VECTRA automation and correlated with clinicopathologic parameters. The Cancer Genome Atlas (TGCA, n = 499) and Gene Expression Omnibus (n = 504) databases were queried for expression, genomic and clinical data. Statistics were performed using SPSSv23. Results Nuclear histone H3K18Ac staining increases in primary cancer (p = 0.05) and further in metastases (p < 0.01) compared to benign on tissue arrays. P300 protein expression increases in cancer (p = 0.04) and metastases (p < 0.001). A progressive decrease in nuclear SIRT2 staining occurs comparing benign to cancer or metastases (p = 0.04 and p = 0.03 respectively). Decreased SIRT2 correlates with higher grade cancer (p = 0.02). Time to Prostate Specific Antigen (PSA) recurrence is shorter in patients exhibiting high compared to low H3K18Ac expression (350 vs. 1542 days respectively, P = 0.03). In GEO, SIRT2 mRNA levels are lower in primary and metastatic tumors (p = 0.01 and 0.001, respectively). TGCA analysis demonstrates SIRT2 deletion in 6% and increasing clinical stage, positive margins and lower PSA recurrence-free survival in patients with SIRT2 loss/deletion (p = 0.01, 0.04 and 0.04 respectively). In this dataset, a correlation between decreasing SIRT2 and increasing P300 mRNA expression occurs in tumor samples (R = −0.46). Conclusions In multiple datasets, decreases in SIRT2 expression portend worse clinicopathologic outcomes. Alterations in SIRT2-H3K18Ac suggest altered P300 activity and identify a subset of tumors that could benefit from histone deacetylation inhibition. |
| first_indexed | 2024-04-12T06:33:46Z |
| format | Article |
| id | doaj.art-6a669ba273564161b5fa1bac5eec0da3 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-04-12T06:33:46Z |
| publishDate | 2017-12-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-6a669ba273564161b5fa1bac5eec0da32022-12-22T03:43:56ZengBMCBMC Cancer1471-24072017-12-011711810.1186/s12885-017-3853-9Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomesShivashankar Damodaran0Nathan Damaschke1Joseph Gawdzik2Bing Yang3Cedric Shi4Glenn O. Allen5Wei Huang6John Denu7David Jarrard8Department of Urology, School of Medicine and Public Health, University of WisconsinDepartment of Urology, School of Medicine and Public Health, University of WisconsinDepartment of Urology, School of Medicine and Public Health, University of WisconsinDepartment of Urology, School of Medicine and Public Health, University of WisconsinDepartment of Urology, School of Medicine and Public Health, University of WisconsinDepartment of Urology, School of Medicine and Public Health, University of WisconsinDepartment of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public HealthCarbone Comprehensive Cancer Center, University of WisconsinDepartment of Urology, School of Medicine and Public Health, University of WisconsinAbstract Background Histones undergo extensive post-translational modifications and this epigenetic regulation plays an important role in modulating transcriptional programs capable of driving cancer progression. Acetylation of histone H3K18, associated with gene activation, is enhanced by P300 and opposed by the deacetylase Sirtuin2 (SIRT2). As these enzymes represent an important target for cancer therapy, we sought to determine whether the underlying genes are altered during prostate cancer (PCa) progression. Methods Tissue microarrays generated from 71 radical prostatectomy patients were initially immunostained for H3K18Ac, P300 and SIRT2. Protein levels were quantified using VECTRA automation and correlated with clinicopathologic parameters. The Cancer Genome Atlas (TGCA, n = 499) and Gene Expression Omnibus (n = 504) databases were queried for expression, genomic and clinical data. Statistics were performed using SPSSv23. Results Nuclear histone H3K18Ac staining increases in primary cancer (p = 0.05) and further in metastases (p < 0.01) compared to benign on tissue arrays. P300 protein expression increases in cancer (p = 0.04) and metastases (p < 0.001). A progressive decrease in nuclear SIRT2 staining occurs comparing benign to cancer or metastases (p = 0.04 and p = 0.03 respectively). Decreased SIRT2 correlates with higher grade cancer (p = 0.02). Time to Prostate Specific Antigen (PSA) recurrence is shorter in patients exhibiting high compared to low H3K18Ac expression (350 vs. 1542 days respectively, P = 0.03). In GEO, SIRT2 mRNA levels are lower in primary and metastatic tumors (p = 0.01 and 0.001, respectively). TGCA analysis demonstrates SIRT2 deletion in 6% and increasing clinical stage, positive margins and lower PSA recurrence-free survival in patients with SIRT2 loss/deletion (p = 0.01, 0.04 and 0.04 respectively). In this dataset, a correlation between decreasing SIRT2 and increasing P300 mRNA expression occurs in tumor samples (R = −0.46). Conclusions In multiple datasets, decreases in SIRT2 expression portend worse clinicopathologic outcomes. Alterations in SIRT2-H3K18Ac suggest altered P300 activity and identify a subset of tumors that could benefit from histone deacetylation inhibition.http://link.springer.com/article/10.1186/s12885-017-3853-9Epigenetic modifications in PCaHistone H3 acetylationCancer progressionSIRT2 loss |
| spellingShingle | Shivashankar Damodaran Nathan Damaschke Joseph Gawdzik Bing Yang Cedric Shi Glenn O. Allen Wei Huang John Denu David Jarrard Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes BMC Cancer Epigenetic modifications in PCa Histone H3 acetylation Cancer progression SIRT2 loss |
| title | Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes |
| title_full | Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes |
| title_fullStr | Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes |
| title_full_unstemmed | Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes |
| title_short | Dysregulation of Sirtuin 2 (SIRT2) and histone H3K18 acetylation pathways associates with adverse prostate cancer outcomes |
| title_sort | dysregulation of sirtuin 2 sirt2 and histone h3k18 acetylation pathways associates with adverse prostate cancer outcomes |
| topic | Epigenetic modifications in PCa Histone H3 acetylation Cancer progression SIRT2 loss |
| url | http://link.springer.com/article/10.1186/s12885-017-3853-9 |
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