Abstract
Background
SIRT1 is a NAD+-dependent deacetylase that plays crucial roles in many biological processes, including stress response, apoptosis, cellular metabolism, adaptation to calorie restriction, aging, and tumorigenesis. The purpose of this study is to elucidate the clinicopathological and functional significance of SIRT1 expression in hepatocellular carcinoma (HCC).
Methods
SIRT1 expression in HCC was determined by immunohistochemical staining. The results were correlated with clinicopathological parameters. SIRT1 was overexpressed in HCC cell line SK-Hep1 to study its role in tumorigenesis and resistance to chemotherapy.
Results
SIRT1 was overexpressed in 95 of 172 HCCs (55%). SIRT1 overexpression was associated with higher α-fetoprotein level, higher tumor grade, and absence of β-catenin mutation. SIRT1 expression predicted poor long-term survival for patients with resected HCC. The elevated SIRT1 protein level in HCC was not attributable to the elevation of mRNA level. The half-life of SIRT1 protein was longer in cell lines with higher expression of SIRT1. We further demonstrated that SIRT1 was degraded by the 26S proteasome in an ubiquitin-dependent manner. Overexpression of SIRT1 promoted tumorigenesis and resistance to chemotherapeutical agent and sorafenib.
Conclusions
SIRT1 is an oncogenic protein for HCC and is a predictor of worse outcome after surgical resection of HCC.
Similar content being viewed by others
References
El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132:2557–76.
Yu MC, Yuan JM, Govindarajan S, Ross RK. Epidemiology of hepatocellular carcinoma. Can J Gastroenterol. 2000;14:703–9.
Hsu HC, Jeng YM, Mao TL, Chu JS, Lai PL, Peng SY. β-catenin mutations are associated with a subset of low-stage hepatocellular carcinoma negative for hepatitis B virus and with favorable prognosis. Am J Pathol. 2000;157:763–70.
Hsu HC, Huang AM, Lai PL, Chien WM, Peng SY, Lin SW. Genetic alterations at the splice junction of p53 gene in human hepatocellular carcinoma. Hepatology. 1994;19:122–8.
Chen D, Steele AD, Lindquist S, Guarente L. Increase in activity during calorie restriction requires Sirt1. Science. 2005;310:1641.
Chua KF, Mostoslavsky R, Lombard DB, Pang WW, Saito S, Franco S, et al. Mammalian SIRT1 limits replicative life span in response to chronic genotoxic stress. Cell Metab. 2005;2:67–76.
Monteiro JP, Cano MI. SIRT1 deacetylase activity and the maintenance of protein homeostasis in response to stress: an overview. Protein Pept Lett. 2011;18:167–73.
Verdin E, Hirschey MD, Finley LW, Haigis MC. Sirtuin regulation of mitochondria: energy production, apoptosis, and signaling. Trends Biochem Sci. 2010;35:669–75.
Vaziri H, Dessain SK, Ng Eaton E, Imai SI, Frye RA, Pandita TK, et al. hSIR2(SIRT1) functions as an NAD-dependent p53 deacetylase. Cell. 2001;107:149–59.
Haigis MC, Sinclair DA. Mammalian sirtuins: biological insights and disease relevance. Annu Rev Pathol. 2010;5:253–95.
Huffman DM, Grizzle WE, Bamman MM, Kim JS, Eltoum IA, Elgavish A, et al. SIRT1 is significantly elevated in mouse and human prostate cancer. Cancer Res. 2007;67:6612–8.
Tseng RC, Lee CC, Hsu HS, Tzao C, Wang YC. Distinct HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma and adenocarcinoma patients. Neoplasia. 2009;11:763–70.
Jang KY, Kim KS, Hwang SH, Kwon KS, Kim KR, Park HS, et al. Expression and prognostic significance of SIRT1 in ovarian epithelial tumours. Pathology. 2009;41:366–71.
Jung-Hynes B, Nihal M, Zhong W, Ahmad N. Role of sirtuin histone deacetylase SIRT1 in prostate cancer. A target for prostate cancer management via its inhibition? J Biol Chem. 2009;284:3823–32.
Liang XJ, Finkel T, Shen DW, Yin JJ, Aszalos A, Gottesman MM. SIRT1 contributes in part to cisplatin resistance in cancer cells by altering mitochondrial metabolism. Mol Cancer Res. 2008;6:1499–506.
Wang RH, Sengupta K, Li C, Cao L, Xiao C, Kim S, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer Cell. 2008;14:312–23.
Firestein R, Blander G, Michan S, Oberdoerffer P, Ogino S, Campbell J, et al. The SIRT1 deacetylase suppresses intestinal tumorigenesis and colon cancer growth. PLoS One. 2008;3:e2020
Wang RH, Zheng Y, Kim HS, Xu X, Cao L, Luhasen T, et al. Interplay among BRCA1, SIRT1, and Survivin during BRCA1-associated tumorigenesis. Mol Cell. 2008;32:11–20.
Chen J, Zhang B, Wong N, Lo AW, To KF, Chan AW, et al. Sirtuin 1 is upregulated in a subset of hepatocellular carcinomas where it is essential for telomere maintenance and tumor cell growth. Cancer Res. 2011;71:4138–49.
Choi HN, Bae JS, Jamiyandorj U, Noh SJ, Park HS, Jang KY, et al. Expression and role of SIRT1 in hepatocellular carcinoma. Oncol Rep. 2011;26:503–10.
Edmonson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 among 489,000 necropsies. Cancer (Phila). 1954;7:462–503.
Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A AJCC cancer staging manual. 7th ed. New York: Springer; 2010
Hong EH, Lee SJ, Kim JS, Lee KH, Um HD, Kim JH, et al. Ionizing radiation induces cellular senescence of articular chondrocytes via negative regulation of SIRT1 by p38 kinase. J Biol Chem. 2010;285:1283–95.
Ford J, Ahmed S, Allison S, Jiang M, Milner J. JNK2-dependent regulation of SIRT1 protein stability. Cell Cycle. 2008;7:3091–7.
Liu T, Liu PY, Marshall GM. The critical role of the class III histone deacetylase SIRT1 in cancer. Cancer Res. 2009;69:1702–5.
Uhl M, Csernok A, Aydin S, Kreienberg R, Wiesmüller L, Gatz SA. Role of SIRT1 in homologous recombination. DNA Repair (Amst). 2010;9:383–93.
Ming M, Shea CR, Guo X, Li X, Soltani K, Han W, et al. Regulation of global genome nucleotide excision repair by SIRT1 through xeroderma pigmentosum C. Proc Natl Acad Sci USA. 2010;107:22623–8.
Palacios JA, Herranz D, De Bonis ML, Velasco S, Serrano M, Blasco MA. SIRT1 contributes to telomere maintenance and augments global homologous recombination. J Cell Biol. 2010;191:1299–313.
Laurent-Puig P, Legoix P, Bluteau O, Belghiti J, Franco D, Binot F, et al. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology. 2001;120:1763–73.
Kalle AM, Mallika A, Badiger J, Alinakhi, Talukdar P, Sachchidanand. Inhibition of SIRT1 by a small molecule induces apoptosis in breast cancer cells. Biochem Biophys Res Commun. 2010;401:13–9.
Ota H, Tokunaga E, Chang K, Hikasa M, Iijima K, Eto M, et al. Sirt1 inhibitor, Sirtinol, induces senescence-like growth arrest with attenuated Ras-MAPK signaling in human cancer cells. Oncogene. 2006;25:176–85.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Chen, HC., Jeng, YM., Yuan, RH. et al. SIRT1 Promotes Tumorigenesis and Resistance to Chemotherapy in Hepatocellular Carcinoma and its Expression Predicts Poor Prognosis. Ann Surg Oncol 19, 2011–2019 (2012). https://doi.org/10.1245/s10434-011-2159-4
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-011-2159-4