TY - JOUR
T1 - Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients
AU - Tseng, Ruo Chia
AU - Lee, Chin Chu
AU - Hsu, Han Shui
AU - Tzao, Ching
AU - Wang, Yi Ching
N1 - Funding Information:
Abbreviations: 5-aza-dC, 5-aza-2′-deoxycytidine; AD, adenocarcinoma; DBC1, deleted in breast cancer 1; H3K9me, histone H3 methylated at Lys9; H3K9ac, histone H3 acetylated at Lys9; HIC1, hypermethylation in cancer 1; MeCP2, methyl CpG binding protein 2; NSCLC, non–small cell lung cancer; SCC, squamous cell carcinomas; SAHA, suberoylanilide hydroxamic acid Address all correspondence to: Yi-Ching Wang, PhD, Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1 University Rd, Tainan 70101, Taiwan, ROC. E-mail: [email protected] 1This work was supported in part by grant NSC96-2628-B-006-048-MY3 from the National Science Council and grant DOH97-TD-G-111-035 from the Department of Health (The Executive Yuan, Republic of China). 2This article refers to supplementary materials, which are designated by Tables W1 to W3 and Figure W1 and are available online at www.neoplasia.com. Received 12 March 2009; Revised 4 May 2009; Accepted 6 May 2009 Copyright © 2009 Neoplasia Press, Inc. All rights reserved 1522-8002/09/$25.00 DOI 10.1593/neo.09470
PY - 2009/8
Y1 - 2009/8
N2 - A HIC1-SIRT1-p53 circular loop in which hypermethylation in cancer 1 (HIC1) represses the transcription of SIRT1 that deacetylates and inactivates p53 thus leading to HIC1 inactivation has been identified in cell and animal models. However, the alteration and prognostic effects of HIC1-SIRT1-p53 circular loop have never been demonstrated in human cancer patients. We examine the HIC1-SIRT1-p53 alterations in 118 lung cancer patients to define their etiological roles in tumorigenesis. We found that patients with lung squamous cell carcinoma with low p53 acetylation and SIRT1 expression mostly showed low HIC1 expression, confirming deregulation of HIC1-SIRT1-p53 circular loop in the clinical model. Interestingly, the expression of deleted in breast cancer 1 (DBC1), which blocks the interaction between SIRT1 deacetylase and p53, led to acetylated p53 in patients with lung adenocarcinoma. However, epigenetic alteration of HIC1 promoter by posttranslational modifications of histones and promoter hypermethylation favoring the compacted chromatin production attenuated the transcriptional induction by acetylated p53. Importantly, lung cancer patients with altered HIC1-SIRT1-p53 circular regulation showed poor prognosis. Our data show the first valid clinical evidence of the deregulation of HIC1-SIRT1-p53 loop in lung tumorigenesis and prognosis. Distinct status of p53 acetylation/deacetylation and HIC1 alteration mechanism result from different SIRT1-DBC1 control and epigenetic alteration in lung squamous cell carcinoma and lung adenocarcinoma.
AB - A HIC1-SIRT1-p53 circular loop in which hypermethylation in cancer 1 (HIC1) represses the transcription of SIRT1 that deacetylates and inactivates p53 thus leading to HIC1 inactivation has been identified in cell and animal models. However, the alteration and prognostic effects of HIC1-SIRT1-p53 circular loop have never been demonstrated in human cancer patients. We examine the HIC1-SIRT1-p53 alterations in 118 lung cancer patients to define their etiological roles in tumorigenesis. We found that patients with lung squamous cell carcinoma with low p53 acetylation and SIRT1 expression mostly showed low HIC1 expression, confirming deregulation of HIC1-SIRT1-p53 circular loop in the clinical model. Interestingly, the expression of deleted in breast cancer 1 (DBC1), which blocks the interaction between SIRT1 deacetylase and p53, led to acetylated p53 in patients with lung adenocarcinoma. However, epigenetic alteration of HIC1 promoter by posttranslational modifications of histones and promoter hypermethylation favoring the compacted chromatin production attenuated the transcriptional induction by acetylated p53. Importantly, lung cancer patients with altered HIC1-SIRT1-p53 circular regulation showed poor prognosis. Our data show the first valid clinical evidence of the deregulation of HIC1-SIRT1-p53 loop in lung tumorigenesis and prognosis. Distinct status of p53 acetylation/deacetylation and HIC1 alteration mechanism result from different SIRT1-DBC1 control and epigenetic alteration in lung squamous cell carcinoma and lung adenocarcinoma.
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U2 - 10.1593/neo.09470
DO - 10.1593/neo.09470
M3 - Article
C2 - 19649206
AN - SCOPUS:67650445737
SN - 1522-8002
VL - 11
SP - 763
EP - 770
JO - Neoplasia
JF - Neoplasia
IS - 8
ER -