Z Gastroenterol 2020; 58(01): e42
DOI: 10.1055/s-0039-3402213
Poster Visit Session IV Tumors: Saturday, February 15, 2020, 8:30 am – 09:15 am, Lecture Hall P1
Georg Thieme Verlag KG Stuttgart · New York

Histone deacetylases (HDAC) expressions in HCC and functional effects of HDAC inhibitors in liver cancer cells

K Freese
1   Friedrich-Alexander University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen, Germany
,
T Seitz
1   Friedrich-Alexander University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen, Germany
,
P Dietrich
1   Friedrich-Alexander University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen, Germany
,
SML Lee
2   Biobank under the administration of the Human Tissue and Cell Research Foundation, Ludwig-Maximilians-University Munich, Department of General Visceral- and Transplantation Surgery, Munich, Germany
,
WE Thasler
3   Hepacult GmbH, Planegg/Martinsried, Germany
,
A Bosserhoff
1   Friedrich-Alexander University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen, Germany
4   Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany
,
C Hellerbrand
1   Friedrich-Alexander University Erlangen-Nürnberg, Institute of Biochemistry, Erlangen, Germany
4   Comprehensive Cancer Center (CCC) Erlangen-EMN, Erlangen, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
03 January 2020 (online)

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Histone deacetylases (HDACs) comprise in humans currently 18 members divided in 4 classes. Histone deacetylase (HDAC) inhibition (HDACi) is emerging as a promising therapeutic strategy. However, most pharmacological HDACi unselectively block different HDAC classes and their molecular mechanisms of action are only incompletely understood.

The aim of this study was to systematically analyse the expressions of different HDAC classes in HCC cells and tissues and to functionally analyze the effect of the HDACi suberanilohydroxamic acid (SAHA) and trichostatin A (TSA) on tumorigenicity of HCC cells.

Methods and Results:

Gene expression of all HDAC classes was significantly increased in human HCC cell lines (Hep3B, HepG2, PLC, HuH7) compared to primary human hepatocytes (PHH). Analysis of HCC patient data showed increased expression of several HDACs in HCC tissues compared to non-tumorous liver. However, there was no unified picture of regulation in three different HCC patient data sets and we observed a strong variation in gene expression of different HDACs in tumorous as well as non-tumorous liver. Still, there was a strong correlation in the expression of HDAC class IIa (HDAC4, 5, 7, 9) as well as HDAC2 and 8 (class I) and HDAC10 (class IIb) and HDAC11 (class IV) in HCC tissues of individual patients. This might indicate a common mechanism of the regulation of these HDACs in HCC. TCGA (The Cancer Genome Atlas) data set analysis revealed that HDAC4, HDAC7 and HDAC9 as well as HDAC class I members HDAC1 and HDAC2 significantly correlated with patients' survival. Furthermore, we observed that SAHA and TSA reduced proliferation, clonogenicity and migratory potential of HCC cells. SAHA but not TSA induced features of senescence in HCC cells. Additionally, HDACi enhanced the efficacy of sorafenib in killing sorafenib susceptible cells. Moreover, HDACi reestablished sorafenib sensitivity in resistant HCC cells. As potential underlying mechanisms of the combined HDACi and sorafenib effects we identified enhanced expression of the cytochrome CYP2E1.

Summary and conclusion:

HDACs are significantly but differently increased in HCC, which may be exploited to develop more targeted therapeutic approaches. HDACi affect different facets of tumorigenicity of HCC cells and appears to be a promising therapeutic approach alone or in combination with sorafenib.