HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population.
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.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
Ser Yeng
SY
Ler
School of Chemical and Life Sciences, Singapore Polytechnic, Singapore, Republic of Singapore.
Carol Ho Wing
CH
Leung
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.
Lay Wai
LW
Khin
School of Public Health, Guangxi Medical University, Nanning, Guangxi, P.R. China.
Guo-Dong
GD
Lu
Cancer Science Institute of Singapore, National University of Singapore, Singapore, Republic of Singapore.
Manuel
M
Salto-Tellez
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Republic of Singapore.
Mikael
M
Hartman
Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Republic of Singapore.
Philip Tsau Choong
PT
Iau
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
Celestial T
CT
Yap
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore.
Shing Chuan
SC
Hooi
D000328:Adult; D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000401:mortality; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D055785:Gene Knockdown Techniques; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000401:mortality; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012044:Regression Analysis; D018570:Risk Assessment; D012846:Singapore
D014408:Biomarkers, Tumor; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2