Histone deacetylase
inhibitors (HDACi) were identified nearly four decades ago based on their
ability to induce cellular differentiation. However, the preclinical and
clinical development of these compounds as cancer therapies has focused almost
entirely on their capacity to induce apoptosis in hematologic and lymphoid
malignancies, often in combination with conventional cytotoxic agents. In many
cases, the doses of HDACi necessary to induce these effects result in
significant toxicity. Prompted by the capacity of osteosarcoma cells to express
markers of terminal osteoblast differentiation in response to DNA
methyltransferase inhibitors, we hypothesized that the epigenetic reprogramming
capacity of HDACi might be exploited for therapeutic benefit. Here, we show
that continuous exposure of osteosarcoma cells to low concentrations of HDACi
LBH589 (Panobinostat) induces terminal osteoblast differentiation and
irreversible senescence over a three-week period without inducing cell death.
Remarkably, transcriptional profiling revealed that HDACi therapy initiated
gene signatures characteristic of chondrocyte and adipocyte lineages in
addition to marked upregulation of mature osteoblast markers. Although histone
and tubulin acetylation was readily detectable in response to HDACi treatment,
we did not observe acetylation of p53, indicating that cell senescence is due
to p53-independent mechanism. In a mouse xenograft model, continuous low dose
treatment with LBH589 induced a sustained cytostatic response accompanied by
marked induction of mature osteoblast gene expression. These data suggest that
the remarkable capacity of osteosarcoma cells to differentiate in response to
HDACi therapy could be exploited for therapeutic benefit without inducing cell
death or systemic toxicity.