SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer

Katsuhiko Nosho, Kaori Shima, Natsumi Irahara, Shoko Kure, Ron Firestein, Yoshifumi Baba, Saori Toyoda, Li Chen, Aditi Hazra, Edward L. Giovannucci, Charles S Fuchs, Shuji Ogino

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Abstract

The class III histone deacetylase SIRT1 (sir2) is important in epigenetic gene silencing. Inhibition of SIRT1 reactivates silenced genes, suggesting a possible therapeutic approach of targeted reversal of aberrantly silenced genes. In addition, SIRT1 may be involved in the well-known link between obesity, cellular energy balance and cancer. However, a comprehensive study of SIRT1 using human cancer tissue with clinical outcome data is currently lacking, and its prognostic significance is uncertain. Using the database of 485 colorectal cancers in two independent prospective cohort studies, we detected SIRT1 overexpression in 180 (37%) tumors by immunohistochemistry. We examined its relationship to the CpG island methylator phenotype (CIMP), related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by MethyLight. SIRT1 overexpression was associated with CIMP-high (6 of 8 methylated CIMP-specific promoters, P0.002) and microsatellite instability (MSI)-high phenotype (P0.0001). In both univariate and multivariate analyses, SIRT1 overexpression was significantly associated with the CIMP-high MSI-high phenotype (multivariate odds ratio, 3.20; 95% confidence interval, 1.35-7.59; P0.008). In addition, mucinous component (P0.01), high tumor grade (P0.02), and fatty acid synthase overexpression (P0.04) were significantly associated with SIRT positivity in multivariate analysis. SIRT1 was not significantly related with age, sex, tumor location, stage, signet ring cells, cyclooxygenase-2 (COX-2), LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53, Β-catenin, COX-2, or patient prognosis. In conclusion, SIRT1 expression is associated with CIMP-high MSI-high colon cancer, suggesting involvement of SIRT1 in gene silencing in this unique tumor subtype.

Original languageEnglish
Pages (from-to)922-932
Number of pages11
JournalModern Pathology
Volume22
Issue number7
DOIs
Publication statusPublished - Jul 2009
Externally publishedYes

Keywords

  • Acetylation
  • Colon cancer
  • Epigenetics
  • HDAC
  • Sir2
  • Sirtuin

Cite this

Nosho, Katsuhiko ; Shima, Kaori ; Irahara, Natsumi ; Kure, Shoko ; Firestein, Ron ; Baba, Yoshifumi ; Toyoda, Saori ; Chen, Li ; Hazra, Aditi ; Giovannucci, Edward L. ; Fuchs, Charles S ; Ogino, Shuji. / SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. In: Modern Pathology. 2009 ; Vol. 22, No. 7. pp. 922-932.
@article{a9799d24bdb34fb0af1a19e67fe89fab,
title = "SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer",
abstract = "The class III histone deacetylase SIRT1 (sir2) is important in epigenetic gene silencing. Inhibition of SIRT1 reactivates silenced genes, suggesting a possible therapeutic approach of targeted reversal of aberrantly silenced genes. In addition, SIRT1 may be involved in the well-known link between obesity, cellular energy balance and cancer. However, a comprehensive study of SIRT1 using human cancer tissue with clinical outcome data is currently lacking, and its prognostic significance is uncertain. Using the database of 485 colorectal cancers in two independent prospective cohort studies, we detected SIRT1 overexpression in 180 (37{\%}) tumors by immunohistochemistry. We examined its relationship to the CpG island methylator phenotype (CIMP), related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by MethyLight. SIRT1 overexpression was associated with CIMP-high (6 of 8 methylated CIMP-specific promoters, P0.002) and microsatellite instability (MSI)-high phenotype (P0.0001). In both univariate and multivariate analyses, SIRT1 overexpression was significantly associated with the CIMP-high MSI-high phenotype (multivariate odds ratio, 3.20; 95{\%} confidence interval, 1.35-7.59; P0.008). In addition, mucinous component (P0.01), high tumor grade (P0.02), and fatty acid synthase overexpression (P0.04) were significantly associated with SIRT positivity in multivariate analysis. SIRT1 was not significantly related with age, sex, tumor location, stage, signet ring cells, cyclooxygenase-2 (COX-2), LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53, Β-catenin, COX-2, or patient prognosis. In conclusion, SIRT1 expression is associated with CIMP-high MSI-high colon cancer, suggesting involvement of SIRT1 in gene silencing in this unique tumor subtype.",
keywords = "Acetylation, Colon cancer, Epigenetics, HDAC, Sir2, Sirtuin",
author = "Katsuhiko Nosho and Kaori Shima and Natsumi Irahara and Shoko Kure and Ron Firestein and Yoshifumi Baba and Saori Toyoda and Li Chen and Aditi Hazra and Giovannucci, {Edward L.} and Fuchs, {Charles S} and Shuji Ogino",
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Nosho, K, Shima, K, Irahara, N, Kure, S, Firestein, R, Baba, Y, Toyoda, S, Chen, L, Hazra, A, Giovannucci, EL, Fuchs, CS & Ogino, S 2009, 'SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer', Modern Pathology, vol. 22, no. 7, pp. 922-932. https://doi.org/10.1038/modpathol.2009.49

SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. / Nosho, Katsuhiko; Shima, Kaori; Irahara, Natsumi; Kure, Shoko; Firestein, Ron; Baba, Yoshifumi; Toyoda, Saori; Chen, Li; Hazra, Aditi; Giovannucci, Edward L.; Fuchs, Charles S; Ogino, Shuji.

In: Modern Pathology, Vol. 22, No. 7, 07.2009, p. 922-932.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer

AU - Nosho, Katsuhiko

AU - Shima, Kaori

AU - Irahara, Natsumi

AU - Kure, Shoko

AU - Firestein, Ron

AU - Baba, Yoshifumi

AU - Toyoda, Saori

AU - Chen, Li

AU - Hazra, Aditi

AU - Giovannucci, Edward L.

AU - Fuchs, Charles S

AU - Ogino, Shuji

PY - 2009/7

Y1 - 2009/7

N2 - The class III histone deacetylase SIRT1 (sir2) is important in epigenetic gene silencing. Inhibition of SIRT1 reactivates silenced genes, suggesting a possible therapeutic approach of targeted reversal of aberrantly silenced genes. In addition, SIRT1 may be involved in the well-known link between obesity, cellular energy balance and cancer. However, a comprehensive study of SIRT1 using human cancer tissue with clinical outcome data is currently lacking, and its prognostic significance is uncertain. Using the database of 485 colorectal cancers in two independent prospective cohort studies, we detected SIRT1 overexpression in 180 (37%) tumors by immunohistochemistry. We examined its relationship to the CpG island methylator phenotype (CIMP), related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by MethyLight. SIRT1 overexpression was associated with CIMP-high (6 of 8 methylated CIMP-specific promoters, P0.002) and microsatellite instability (MSI)-high phenotype (P0.0001). In both univariate and multivariate analyses, SIRT1 overexpression was significantly associated with the CIMP-high MSI-high phenotype (multivariate odds ratio, 3.20; 95% confidence interval, 1.35-7.59; P0.008). In addition, mucinous component (P0.01), high tumor grade (P0.02), and fatty acid synthase overexpression (P0.04) were significantly associated with SIRT positivity in multivariate analysis. SIRT1 was not significantly related with age, sex, tumor location, stage, signet ring cells, cyclooxygenase-2 (COX-2), LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53, Β-catenin, COX-2, or patient prognosis. In conclusion, SIRT1 expression is associated with CIMP-high MSI-high colon cancer, suggesting involvement of SIRT1 in gene silencing in this unique tumor subtype.

AB - The class III histone deacetylase SIRT1 (sir2) is important in epigenetic gene silencing. Inhibition of SIRT1 reactivates silenced genes, suggesting a possible therapeutic approach of targeted reversal of aberrantly silenced genes. In addition, SIRT1 may be involved in the well-known link between obesity, cellular energy balance and cancer. However, a comprehensive study of SIRT1 using human cancer tissue with clinical outcome data is currently lacking, and its prognostic significance is uncertain. Using the database of 485 colorectal cancers in two independent prospective cohort studies, we detected SIRT1 overexpression in 180 (37%) tumors by immunohistochemistry. We examined its relationship to the CpG island methylator phenotype (CIMP), related molecular events, clinical features including body mass index, and patient survival. We quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1) and eight other CpG islands (CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN) by MethyLight. SIRT1 overexpression was associated with CIMP-high (6 of 8 methylated CIMP-specific promoters, P0.002) and microsatellite instability (MSI)-high phenotype (P0.0001). In both univariate and multivariate analyses, SIRT1 overexpression was significantly associated with the CIMP-high MSI-high phenotype (multivariate odds ratio, 3.20; 95% confidence interval, 1.35-7.59; P0.008). In addition, mucinous component (P0.01), high tumor grade (P0.02), and fatty acid synthase overexpression (P0.04) were significantly associated with SIRT positivity in multivariate analysis. SIRT1 was not significantly related with age, sex, tumor location, stage, signet ring cells, cyclooxygenase-2 (COX-2), LINE-1 hypomethylation, KRAS, BRAF, BMI, PIK3CA, HDAC, p53, Β-catenin, COX-2, or patient prognosis. In conclusion, SIRT1 expression is associated with CIMP-high MSI-high colon cancer, suggesting involvement of SIRT1 in gene silencing in this unique tumor subtype.

KW - Acetylation

KW - Colon cancer

KW - Epigenetics

KW - HDAC

KW - Sir2

KW - Sirtuin

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