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.
OBJECTIVE
Recently, several studies reported a strong functional link between histone deacetylases (HDAC) and the development of tumors of the large intestine. However, despite the importance of these molecules, comparably little is known on expression patterns and functions of specific HDAC isoforms in colorectal cancer.


METHODS
We characterized class I HDAC isoform expression patterns in a cohort of 140 colorectal carcinomas by immunohistochemistry. In addition, effects of HDAC inhibition by valproic acid and suberoylanilide hydroxamic acid, and specific HDAC isoform knockdown by short interfering RNA, were investigated in a cell culture model.


RESULTS
We found class I HDACs highly expressed in a subset of colorectal carcinomas with positivity for HDAC1 in 36.4%, HDAC2 in 57.9%, and HDAC3 in 72.9% of cases. Expression was significantly enhanced in strongly proliferating (P = 0.002), dedifferentiated (P = 0.022) tumors. High HDAC expression levels implicated significantly reduced patient survival (P = 0.001), with HDAC2 expression being an independent survival prognosticator (hazard ratio, 2.6; P = 0.03). Short interfering RNA-based inhibition of HDAC1 and HDAC2 but not HDAC3 suppressed growth of colon cancer cells in vitro, although to a lesser extent than chemical HDAC inhibitors did.


CONCLUSIONS
The strong prognostic impact of HDAC isoforms in colorectal cancer, the interactions of HDACs with tumor cell proliferation and differentiation in vivo, and our finding that HDACs are differentially expressed in colorectal tumors suggest that the evaluation of HDAC expression in clinical trials for HDAC inhibitors might help to identify a patient subgroup who will exceptionally profit from such a treatment.
Weichert
Wilko
W
Institut für Pathologie, Charité Universitätsmedizin, Berlin, Germany. wilko.weichert@charite.de
Röske
Annika
A
Niesporek
Silvia
S
Noske
Aurelia
A
Buckendahl
Ann-Christin
AC
Dietel
Manfred
M
Gekeler
Volker
V
Boehm
Markus
M
Beckers
Thomas
T
Denkert
Carsten
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D002277:Carcinoma / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000378:metabolism / Q000401:mortality; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D045325:HCT116 Cells; D019073:HT29 Cells; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000145:classification / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008875:Middle Aged; D011379:Prognosis; D034741:RNA, Small Interfering / Q000494:pharmacology; D016019:Survival Analysis; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D007527:Isoenzymes; D034741:RNA, Small Interfering; D006655:Histone Deacetylases