HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model
in a Southeast Asian population

Ler,Ser  Yeng; Leung,Carol  Ho Wing; Khin,Lay  Wai; Lu,Guo-Dong; Salto-Tellez,Manuel; Hartman,Mikael; Iau,Philip  Tsau Choong; Yap,Celestial  T.; Hooi,Shing  Chuan

doi:10.3892/or.2015.4263

HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population

Authors:
- Ser Yeng Ler
- Carol Ho Wing Leung
- Lay Wai Khin
- Guo-Dong Lu
- Manuel Salto-Tellez
- Mikael Hartman
- Philip Tsau Choong Iau
- Celestial T. Yap
- Shing Chuan Hooi
View Affiliations

Affiliations: Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore, School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, Republic of Singapore, Investigational Medicine Unit, Dean's Office, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Republic of Singapore, School of Public Health, Guangxi Medical University, Nanning, Guangxi, P.R. China, Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore, Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Republic of Singapore
Published online on: September 9, 2015 https://doi.org/10.3892/or.2015.4263
Pages: 2238-2250
Copyright: © Ler et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Histone deacetylases (HDACs) are enzymes involved in transcriptional repression. We aimed to examine the significance of HDAC1 and HDAC2 gene expression in the prediction of recurrence and survival in 156 patients with hepatocellular carcinoma (HCC) among a South East Asian population who underwent curative surgical resection in Singapore. We found that HDAC1 and HDAC2 were upregulated in the majority of HCC tissues. The presence of HDAC1 in tumor tissues was correlated with poor tumor differentiation. Notably, HDAC1 expression in adjacent non-tumor hepatic tissues was correlated with the presence of satellite nodules and multiple lesions, suggesting that HDAC1 upregulation within the field of HCC may contribute to tumor spread. Using competing risk regression analysis, we found that increased cancer-specific mortality was significantly associated with HDAC2 expression. Mortality was also increased with high HDAC1 expression. In the liver cancer cell lines, HEP3B, HEPG2, PLC5, and a colorectal cancer cell line, HCT116, the combined knockdown of HDAC1 and HDAC2 increased cell death and reduced cell proliferation as well as colony formation. In contrast, knockdown of either HDAC1 or HDAC2 alone had minimal effects on cell death and proliferation. Taken together, our study suggests that both HDAC1 and HDAC2 exert pro-survival effects in HCC cells, and the combination of isoform-specific HDAC inhibitors against both HDACs may be effective in targeting HCC to reduce mortality.

View Figures

View References

1	Ito K and Adcock IM: Histone acetylation and histone deacetylation. Mol Biotechnol. 20:99–106. 2002. View Article : Google Scholar : PubMed/NCBI
2	Glass CK and Rosenfeld MG: The coregulator exchange in transcriptional functions of nuclear receptors. Genes Dev. 14:121–141. 2000.PubMed/NCBI
3	Ropero S and Esteller M: The role of histone deacetylases (HDACs) in human cancer. Mol Oncol. 1:19–25. 2007. View Article : Google Scholar : PubMed/NCBI
4	Yang XJ and Seto E: The Rpd3/Hda1 family of lysine deacetylases: From bacteria and yeast to mice and men. Nat Rev Mol Cell Biol. 9:206–218. 2008. View Article : Google Scholar : PubMed/NCBI
5	Johnstone RW: Histone-deacetylase inhibitors: Novel drugs for the treatment of cancer. Nat Rev Drug Discov. 1:287–299. 2002. View Article : Google Scholar : PubMed/NCBI
6	Lagger G, O'Carroll D, Rembold M, Khier H, Tischler J, Weitzer G, Schuettengruber B, Hauser C, Brunmeir R, Jenuwein T, et al: Essential function of histone deacetylase 1 in proliferation control and CDK inhibitor repression. EMBO J. 21:2672–2681. 2002. View Article : Google Scholar : PubMed/NCBI
7	Harms KL and Chen X: Histone deacetylase 2 modulates p53 transcriptional activities through regulation of p53-DNA binding activity. Cancer Res. 67:3145–3152. 2007. View Article : Google Scholar : PubMed/NCBI
8	Lei WW, Zhang KH, Pan XC, Wang DM, Hu Y, Yang YN and Song JG: Histone deacetylase 1 and 2 differentially regulate apoptosis by opposing effects on extracellular signal-regulated kinase 1/2. Cell Death Dis. 1:e442010. View Article : Google Scholar
9	Weichert W: HDAC expression and clinical prognosis in human malignancies. Cancer Lett. 280:168–176. 2009. View Article : Google Scholar
10	Ramsey MR, He L, Forster N, Ory B and Ellisen LW: Physical association of HDAC1 and HDAC2 with p63 mediates transcriptional repression and tumor maintenance in squamous cell carcinoma. Cancer Res. 71:4373–4379. 2011. View Article : Google Scholar : PubMed/NCBI
11	Buurman R, Gürlevik E, Schäffer V, Eilers M, Sandbothe M, Kreipe H, Wilkens L, Schlegelberger B, Kühnel F and Skawran B: Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology. 143:811–820. e1–e15. 2012. View Article : Google Scholar : PubMed/NCBI
12	Fritzsche FR, Weichert W, Röske A, Gekeler V, Beckers T, Stephan C, Jung K, Scholman K, Denkert C, Dietel M, et al: Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer. BMC Cancer. 8:3812008. View Article : Google Scholar : PubMed/NCBI
13	Weichert W, Röske A, Gekeler V, Beckers T, Stephan C, Jung K, Fritzsche FR, Niesporek S, Denkert C, Dietel M, et al: Histone deacetylases 1, 2 and 3 are highly expressed in prostate cancer and HDAC2 expression is associated with shorter PSA relapse time after radical prostatectomy. Br J Cancer. 98:604–610. 2008. View Article : Google Scholar : PubMed/NCBI
14	Weichert W, Röske A, Niesporek S, Noske A, Buckendahl AC, Dietel M, Gekeler V, Boehm M, Beckers T and Denkert C: Class I histone deacetylase expression has independent prognostic impact in human colorectal cancer: Specific role of class I histone deacetylases in vitro and in vivo. Clin Cancer Res. 14:1669–1677. 2008. View Article : Google Scholar : PubMed/NCBI
15	El-Serag HB and Rudolph KL: Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology. 132:2557–2576. 2007. View Article : Google Scholar : PubMed/NCBI
16	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
17	Lau WY: The history of liver surgery. J R Coll Surg Edinb. 42:303–309. 1997.PubMed/NCBI
18	Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, et al: SHARP Investigators Study Group: Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 359:378–390. 2008. View Article : Google Scholar : PubMed/NCBI
19	Portolani N, Coniglio A, Ghidoni S, Giovanelli M, Benetti A, Tiberio GA and Giulini SM: Early and late recurrence after liver resection for hepatocellular carcinoma: Prognostic and therapeutic implications. Ann Surg. 243:229–235. 2006. View Article : Google Scholar : PubMed/NCBI
20	Rahbari NN, Koch M, Schmidt T, Motschall E, Bruckner T, Weidmann K, Mehrabi A, Büchler MW and Weitz J: Meta- analysis of the clamp-crushing technique for transection of the parenchyma in elective hepatic resection: Back to where we started? Ann Surg Oncol. 16:630–639. 2009. View Article : Google Scholar : PubMed/NCBI
21	Barlow WE and Prentice RL: Residuals for relative risk regression. Biometrika. 75:65–74. 1988. View Article : Google Scholar
22	Fisher LD and Lin DY: Time-dependent covariates in the Cox proportional-hazards regression model. Annu Rev Public Health. 20:145–157. 1999. View Article : Google Scholar : PubMed/NCBI
23	Noh JH, Bae HJ, Eun JW, Shen Q, Park SJ, Kim HS, Nam B, Shin WC, Lee EK, Lee K, et al: HDAC2 provides a critical support to malignant progression of hepatocellular carcinoma through feedback control of mTORC1 and AKT. Cancer Res. 74:1728–1738. 2014. View Article : Google Scholar : PubMed/NCBI
24	Quint K, Agaimy A, Di Fazio P, Montalbano R, Steindorf C, Jung R, Hellerbrand C, Hartmann A, Sitter H, Neureiter D, et al: Clinical significance of histone deacetylases 1, 2, 3, and 7: HDAC2 is an independent predictor of survival in HCC. Virchows Arch. 459:129–139. 2011. View Article : Google Scholar : PubMed/NCBI
25	Song J, Noh JH, Lee JH, Eun JW, Ahn YM, Kim SY, Lee SH, Park WS, Yoo NJ, Lee JY, et al: Increased expression of histone deacetylase 2 is found in human gastric cancer. APMIS. 113:264–268. 2005. View Article : Google Scholar : PubMed/NCBI
26	Rikimaru T, Taketomi A, Yamashita Y, Shirabe K, Hamatsu T, Shimada M and Maehara Y: Clinical significance of histone deacetylase 1 expression in patients with hepatocellular carcinoma. Oncology. 72:69–74. 2007. View Article : Google Scholar : PubMed/NCBI
27	Chang HH, Chiang CP, Hung HC, Lin CY, Deng YT and Kuo MY: Histone deacetylase 2 expression predicts poorer prognosis in oral cancer patients. Oral Oncol. 45:610–614. 2009. View Article : Google Scholar
28	Weichert W, Röske A, Gekeler V, Beckers T, Ebert MP, Pross M, Dietel M, Denkert C and Röcken C: Association of patterns of class I histone deacetylase expression with patient prognosis in gastric cancer: A retrospective analysis. Lancet Oncol. 9:139–148. 2008. View Article : Google Scholar : PubMed/NCBI
29	Koh WP, Robien K, Wang R, Govindarajan S, Yuan JM and Yu MC: Smoking as an independent risk factor for hepatocellular carcinoma: The Singapore Chinese Health Study. Br J Cancer. 105:1430–1435. 2011. View Article : Google Scholar : PubMed/NCBI
30	Kang H, Gillespie TW, Goodman M, Brodie SA, Brandes M, Ribeiro M, Ramalingam SS, Shin DM, Khuri FR and Brandes JC: Long-term use of valproic acid in US veterans is associated with a reduced risk of smoking-related cases of head and neck cancer. Cancer. 120:1394–1400. 2014. View Article : Google Scholar : PubMed/NCBI
31	Yamaguchi T, Cubizolles F, Zhang Y, Reichert N, Kohler H, Seiser C and Matthias P: Histone deacetylases 1 and 2 act in concert to promote the G1-to-S progression. Genes Dev. 24:455–469. 2010. View Article : Google Scholar : PubMed/NCBI
32	Noh JH, Jung KH, Kim JK, Eun JW, Bae HJ, Xie HJ, Chang YG, Kim MG, Park WS, Lee JY, et al: Aberrant regulation of HDAC2 mediates proliferation of hepatocellular carcinoma cells by deregulating expression of G1/S cell cycle proteins. PLoS One. 6:e281032011. View Article : Google Scholar : PubMed/NCBI
33	Aghdassi A, Sendler M, Guenther A, Mayerle J, Behn CO, Heidecke CD, Friess H, Büchler M, Evert M, Lerch MM, et al: Recruitment of histone deacetylases HDAC1 and HDAC2 by the transcriptional repressor ZEB1 downregulates E-cadherin expression in pancreatic cancer. Gut. 61:439–448. 2012. View Article : Google Scholar