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

doi:10.1038/modpathol.2009.49

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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96 Scopus citations

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 language	English (US)
Pages (from-to)	922-932
Number of pages	11
Journal	Modern Pathology
Volume	22
Issue number	7
DOIs	https://doi.org/10.1038/modpathol.2009.49
State	Published - Jul 2009
Externally published	Yes

Bibliographical note

Funding Information:
We thank the Nurses’ Health Study and Health Professionals Follow-up Study cohort participants who generously agreed to provide us with biological specimens and information through responses to questionnaires. We also thank Frank Speizer, Walter Willett, Susan Hankinson, Graham Colditz, Meir Stampfer, and many other staff members who implemented and have maintained the cohort studies. This work was supported by US National Institute of Health (NIH) grants P01 CA87969, P01 CA55075, P50 CA127003 (to CSF) and K07 CA122826 (to SO), and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance (NCCRA). KN was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.

Keywords

Acetylation
Colon cancer
Epigenetics
HDAC
Sir2
Sirtuin

UN SDGs

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Nosho, K., Shima, K., Irahara, N., Kure, S., Firestein, R., Baba, Y., Toyoda, S., Chen, L., Hazra, A., Giovannucci, E. L., Fuchs, C. S., & Ogino, S. (2009). SIRT1 histone deacetylase expression is associated with microsatellite instability and CpG island methylator phenotype in colorectal cancer. Modern Pathology, 22(7), 922-932. https://doi.org/10.1038/modpathol.2009.49

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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.",

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",

note = "Funding Information: We thank the Nurses{\textquoteright} Health Study and Health Professionals Follow-up Study cohort participants who generously agreed to provide us with biological specimens and information through responses to questionnaires. We also thank Frank Speizer, Walter Willett, Susan Hankinson, Graham Colditz, Meir Stampfer, and many other staff members who implemented and have maintained the cohort studies. This work was supported by US National Institute of Health (NIH) grants P01 CA87969, P01 CA55075, P50 CA127003 (to CSF) and K07 CA122826 (to SO), and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance (NCCRA). KN was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.",

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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

N1 - Funding Information: We thank the Nurses’ Health Study and Health Professionals Follow-up Study cohort participants who generously agreed to provide us with biological specimens and information through responses to questionnaires. We also thank Frank Speizer, Walter Willett, Susan Hankinson, Graham Colditz, Meir Stampfer, and many other staff members who implemented and have maintained the cohort studies. This work was supported by US National Institute of Health (NIH) grants P01 CA87969, P01 CA55075, P50 CA127003 (to CSF) and K07 CA122826 (to SO), and in part by grants from the Bennett Family Fund and from the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance (NCCRA). KN was supported by a fellowship grant from the Japan Society for Promotion of Science. The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.

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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.

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KW - Epigenetics

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

Abstract

Bibliographical note

Keywords

UN SDGs

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