SIRT7, H3K18ac, and ELK4 Immunohistochemical Expression in Hepatocellular Carcinoma
1
조회
0
다운로드
0
인용
0
참고문헌
키워드
초록
Background: SIRT7 is one of the histone deacetylases and is NAD-dependent. It forms a complex with ETS-like transcription factor 4 (ELK4), which deacetylates H3K18ac and works as a transcriptional suppressor. Overexpression of SIRT7 and deacetylation of H3K18ac have been shown to be associated with aggressive clinical behavior in some cancers, including hepatocellular carcinoma (HCC). The present study investigated the immunohistochemical expression of SIRT7, H3K18ac, and ELK4 in hepatocellular carcinoma. Methods: A total of 278 HCC patients were enrolled in this study. Tissue microarray blocks were made from existing paraffin-embedded blocks. Immunohistochemical expressions of SIRT7, H3K18ac and ELK4 were scored and analyzed. Results: High SIRT7 (p = .034), high H3K18ac (p = .001), and low ELK4 (p = .021) groups were associated with poor outcomes. Age < 65 years (p = .028), tumor size ≥ 5 cm (p = .001), presence of vascular emboli (p = .003), involvement of surgical margin (p = .001), and high American Joint Committee on Cancer stage (III&V) (p < .001) were correlated with worse prognoses. In multivariate analysis, H3K18ac (p = .001) and ELK4 (p = .015) were the significant independent prognostic factors. Conclusions: High SIRT7 expression with poor overall survival implies that deacetylation of H3K18ac contributes to progression of HCC. High H3K18ac expression with poor prognosis is predicted due to a compensation mechanism. In addition, high ELK4 expression with good prognosis suggests another role of ELK4 as a tumor suppressor beyond SIRT7’s helper. In conclusion, we could assume that the H3K18ac deacetylation pathway is influenced by many other factors.
Abstract
Background: SIRT7 is one of the histone deacetylases and is NAD-dependent. It forms a complex with ETS-like transcription factor 4 (ELK4), which deacetylates H3K18ac and works as a transcriptional suppressor. Overexpression of SIRT7 and deacetylation of H3K18ac have been shown to be associated with aggressive clinical behavior in some cancers, including hepatocellular carcinoma (HCC). The present study investigated the immunohistochemical expression of SIRT7, H3K18ac, and ELK4 in hepatocellular carcinoma. Methods: A total of 278 HCC patients were enrolled in this study. Tissue microarray blocks were made from existing paraffin-embedded blocks. Immunohistochemical expressions of SIRT7, H3K18ac and ELK4 were scored and analyzed. Results: High SIRT7 (p = .034), high H3K18ac (p = .001), and low ELK4 (p = .021) groups were associated with poor outcomes. Age < 65 years (p = .028), tumor size ≥ 5 cm (p = .001), presence of vascular emboli (p = .003), involvement of surgical margin (p = .001), and high American Joint Committee on Cancer stage (III&V) (p < .001) were correlated with worse prognoses. In multivariate analysis, H3K18ac (p = .001) and ELK4 (p = .015) were the significant independent prognostic factors. Conclusions: High SIRT7 expression with poor overall survival implies that deacetylation of H3K18ac contributes to progression of HCC. High H3K18ac expression with poor prognosis is predicted due to a compensation mechanism. In addition, high ELK4 expression with good prognosis suggests another role of ELK4 as a tumor suppressor beyond SIRT7’s helper. In conclusion, we could assume that the H3K18ac deacetylation pathway is influenced by many other factors.
참고문헌 (36)
- 정규원, "Cancer Statistics in Korea: Incidence, Mortality, Survival, and Prevalence in 2011", Cancer Research and Treatment, 46(2), pp.109~123 (2014), 대한암학회
- 김형석, "Histone Deacetylases and Their Regulatory MicroRNAs in Hepatocarcinogenesis", Journal of Korean Medical Science, 30(10), pp.1375~1380 (2015), 대한의학회
- Ma L, "Epigenetics in hepatocellular carcinoma: an update and future therapy perspectives", World J Gastroenterol, 20, pp.333~345 (2014)
- Hung SY, "Histone-modifying genes as biomarkers in hepatocellular carcinoma", Int J Clin Exp Pathol, 7, pp.2496~2507 (2014)
- Li L, "The controversial role of sirtuins in tumorigenesis: SIRT7 joins the debate", Cell Res, 23, pp.10~12 (2013)
- Mellini P, "Sirtuin modulators: an updated patent review (2012 - 2014)", Expert Opin Ther Pat, 25, pp.5~15 (2015)
- Kleszcz R, "Targeting aberrant cancer metabolism: the role of sirtuins", Pharmacol Rep, 67, pp.1068~1080 (2015)
- Jang KY, "SIRT1 and c-Myc promote liver tumor cell survival and predict poor survival of human hepatocellular carcinomas", PLoS One, 7, pp.E45119~ (2012)
- Chen J, "SIRT2 overexpression in hepatocellular carcinoma mediates epithelial to mesenchymal transition by protein kinase B", glycogen synthase kinase-3beta, Hepatology, pp.2013, 57[DOI]
- Zhang B, "SIRT3 expression in hepatocellular carcinoma and its impact on proliferation and invasion of hepatoma cells", Asian Pac J Trop Med, 6, pp.649~652 (2013)
- Zhang ZG, "Sirt6 suppresses hepatocellular carcinoma cell growth via inhibiting the extracellular signalregulated kinase signaling pathway", Mol Med Rep, 9, pp.882~888 (2014)
- Kim JK, "Sirtuin7 oncogenic potential in human hepatocellular carcinoma and its regulation by the tumor suppressors MiR-125a-5p and MiR-125b", Hepatology, 57, pp.1055~1067 (2013)
- Zheng Y, "MiR-376a and histone deacetylation 9 form a regulatory circuitry in hepatocellular carcinoma", Cell Physiol Biochem, 35, pp.729~739 (2015)
- Barber MF, "SIRT7 links H3K18 deacetylation to maintenance of oncogenic transformation", Nature, 487, pp.114~118 (2012)
- Buchwalter G, "Ets ternary complex transcription factors", Gene, 324, pp.1~14 (2004)
- Edge SB, "AJCC cancer staging manual" (2010), Springer
- Edmondson HA, "Primary carcinoma of the liver: a study of 100 cases among 48,900 necropsies", Cancer, 7, pp.462~503 (1954)
- Eskandarian HA, "A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection", Science, 341, pp.1238858~ (2013)
- Tasselli L, "SIRT6 deacetylates H3K18ac at pericentric chromatin to prevent mitotic errors and cellular senescence", Nat Struct Mol Biol, 23, pp.434~440 (2016)
- Vakhrusheva O, "Sirt7 increases stress resistance of cardiomyocytes and prevents apoptosis and inflammatory cardiomyopathy in mice", Circ Res, 102, pp.703~710 (2008)
- Pokholok DK, "Genome-wide map of nucleosome acetylation and methylation in yeast", Cell, 122, pp.517~527 (2005)
- Sinha I, "Genome-wide patterns of histone modifications in fission yeast", Chromosome Res, 14, pp.95~105 (2006)
- Juliano CN, "H4K12 and H3K18 acetylation associates with poor prognosis in pancreatic cancer", Appl Immunohistochem Mol Morphol, 24, pp.337~344 (2016)
- Tzao C, "Prognostic significance of global histone modifications in resected squamous cell carcinoma of the esophagus", Mod Pathol, 22, pp.252~260 (2009)
- Liu BL, "Global histone modification patterns as prognostic markers to classify glioma patients", Cancer Epidemiol Biomarkers Prev, 19, pp.2888~2896 (2010)
- Seligson DB, "Global histone modification patterns predict risk of prostate cancer recurrence", Nature, 435, pp.1262~1266 (2005)
- Seligson DB, "Global levels of histone modifications predict prognosis in different cancers", Am J Pathol, 174, pp.1619~1628 (2009)
- Liu JP, "Stressed SIRT7: facing a crossroad of senescence and immortality", Clin Exp Pharmacol Physiol, 42, pp.567~569 (2015)
- Malik S, "SIRT7 inactivation reverses metastatic phenotypes in epithelial and mesenchymal tumors", Sci Rep, 5, pp.9841~ (2015)
- Sharrocks AD, "ETS-domain transcription factor family", Nat Rev Mol Cell Biol, 2, pp.827~837 (2001)
- Criqui-Filipe P, "Net, a negative Ras-switchable TCF, contains a second inhibition domain, the CID, that mediates repression through interactions with CtBP and deacetylation", EMBO J, 18, pp.3392~3403 (1999)
- Maira SM, "Net (ERP", SAP2) one of the Rasinducible TCFs, has a novel inhibitory domain with resemblance to the helix-loop-helix motif, 1996, pp.15, 5849~5865
- van Riggelen J, "Loss of net as repressor leads to constitutive increased c-fos transcription in cervical cancer cells", J Biol Chem, 280, pp.3286~3294 (2005)
- Stinson J, "Regulation of TCF ETS-domain transcription factors by helix-loophelix motifs", Nucleic Acids Res, 31, pp.4717~4728 (2003)
- Yates PR, "Id helix-loop-helix proteins inhibit nucleoprotein complex formation by the TCF ETS-domain transcription factors", EMBO J, 18, pp.968~976 (1999)
- Kaikkonen S, "SUMOylation can regulate the activity of ETS-like transcription factor 4", Biochim Biophys Acta, 1799, pp.555~560 (2010)