Histone deacetylase inhibitors (HDACis) inhibit tumor cell growth
and survival, possibly through their ability to regulate the expression
of specific proliferative and/or apoptotic genes. However, the
HDACi-regulated genes necessary and/or sufficient for their biological
effects remain undefined. We demonstrate that the HDACis suberoylanilide
hydroxamic acid (SAHA) and depsipeptide regulate a highly overlapping
gene set with at least 22% of genes showing altered expression
over a 16-h culture period. SAHA and depsipeptide coordinately
regulated the expression of several genes within distinct apoptosis
and cell cycle pathways. Multiple genes within the Myc, type beta
TGF, cyclin/cyclin-dependent kinase, TNF, Bcl-2, and caspase pathways
were regulated in a manner that favored induction of apoptosis
and decreased cellular proliferation. APAF-1, a gene central to
the intrinsic apoptotic pathway, was induced by SAHA and depsipeptide
and shown to be important, but not essential, for HDACi-induced
cell death. Overexpression of p16(INK4A) and arrest of cells in
G(1) can suppress HDACi-mediated apoptosis. Although p16(INK4A)
did not affect the genome-wide transcription changes mediated
by SAHA, a small number of apoptotic genes, including BCLXL and
B-MYB, were differentially regulated in a manner consistent with
attenuated HDACi-mediated apoptosis in arrested cells. We demonstrate
that different HDACi alter transcription of a large and common
set of genes that control diverse molecular pathways important
for cell survival and proliferation. The ability of HDACi to target
multiple apoptotic and cell proliferation pathways may provide
a competitive advantage over other chemotherapeutic agents because
suppression/loss of a single pathway may not confer resistance
to these agents.