Specific and redundant functions of histone deacetylases in regulation of cell cycle and apoptosis.
Inappropriate control of expression of genetic information is the cause of many forms of cancer. Aberrant transcriptional repression by recruitment of histone deacetylases (HDACs) is a key step in pathogenesis of myeloid leukemia. We recently reported that development of colonic cancer involves alterations in the transcriptional repression machinery by increased expression of HDAC2 upon loss of the APC tumor suppressor. Increased expression of HDAC2 is essential for prevention of apoptosis of HT-29 colonic cancer cells. We now discuss whether HDAC2 also plays a role for aberrant cell cycle regulation and expression of the p21(Cip/Waf) cell cycle inhibitor. Whereas inhibition of HDACs by valproic acid or trichostatin A increases p21 expression, selective interference with HDAC2 by siRNA transfection or reconstitution of wildtype APC does not affect p21 expression. Likewise, treatment of HT-29 cells with the HDAC inhibitor valproic acid leads to a moderate inhibition of cell cycle progression in the G1 phase whereas interference with HDAC2 expression does not. Thus, HDAC2 appears to serve a preferential role in the prevention of apoptosis and not in cell cycle control similar to the specific importance of HDAC1 for cell cycle regulation or HDAC 9 for the stress response of the heart.
Zhu
Ping
P
Forschungszentrum Karlsruhe, Institute of Toxicology and Genetics, Eggenstein, Germany.
Huber
Evamaria
E
Kiefer
Franz
F
Göttlicher
Martin
M
D017209:Apoptosis; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D034741:RNA, Small Interfering / Q000235:genetics
D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D006655:Histone Deacetylases