Hijacking HES1: how tumors co-opt the anti-differentiation strategies of quiescent cells

Quiescent and tumor cells share the ability to evade irreversible cell fates. Recent studies have shown that the transcriptional regulator Hairy and Enhancer of Split 1 (HES1) protects quiescent fibroblasts from differentiation or senescence. HES1 is highly expressed in rhabdomyosarcomas, and the inhibition of HES1 restores differentiation in these cells. Pathways that lead to elevated HES1 levels, such as the Notch and Hedgehog pathways, are frequently upregulated in tumors. Compounds that inhibit these pathways induce differentiation and apoptosis in cancer cells and several are in clinical trials. HES1 might repress gene expression in part by recruiting histone deacetylases (HDACs). HDACs inhibit differentiation, whereas histone deacetylase inhibitors (HDACis) induce differentiation or apoptosis in tumors and are also showing promise as therapeutics. Small molecules that directly target HES1 itself were recently identified. Here, we discuss the importance of HES1 function in quiescent and tumor cells. Elucidating the pathways that control quiescence could provide valuable information not only for treating cancer but also other diseases.

Introduction

From one perspective, quiescent cells, which include fibroblasts, lymphocytes, hepatocytes, stem cells and germ cells, are unarguably distinct from cancer cells. Whereas quiescent cells respond to antiproliferative signals from the environment by inducing cell cycle arrest, cancer cells fail to respond to such cues and continue to proliferate unabated [1]. From another perspective, however, cancer and quiescent cells actually share some similarities. Quiescent cells retain the capacity to re-enter the cell cycle upon receiving the appropriate cues and, therefore, must ensure that they do not commit to typically irreversible pathways such as senescence, differentiation or apoptosis (Figure 1). Similarly, a subset of cells within a tumor can also remain in a non-dividing state of tumor dormancy. These cells, which might represent cancer stem cells, have been reported to exist in a quiescent state and to be relatively resistant to traditional chemotherapeutic agents, which are generally designed to kill proliferating cells 2, 3. During dormancy, cancer cells endure conditions of low oxygen, acidic pH and nutrient deficiencies inside a tumor 4, 5. Then, for reasons that remain unclear, these cells can become activated, proliferate and can form a secondary tumor. For many tumor types, the presence of cells that might represent dormant tumor cells is closely associated with subsequent metastatic relapse [6]. Thus, an ability to survive in a reversible, out-of-cycle state is central to both quiescence and cancer.

Accumulating evidence suggests that quiescence, instead of being a passive default state, is actively maintained by specific molecular mechanisms 7, 8. Using DNA microarrays, molecular signatures of quiescence in hematopoietic stem cells [9], lymphocytes [8] and fibroblasts [10] have been identified. These studies have revealed that quiescence is associated with both the downregulation and upregulation of a large number of transcripts. Gene expression changes have also been monitored in human diploid fibroblasts that enter quiescence in response to one of three independent signals: loss of adhesion, contact inhibition and mitogen withdrawal [11]. With each of these antiproliferative signals, there is a major reprogramming of gene expression. Among the gene expression changes that occur are some that are likely to enforce the non-dividing state, for instance, the regulation of molecules that are involved in cell division itself. Other gene expression changes might ensure the reversibility of quiescence, for instance, by protecting cells from the damage induced by free radicals [11]. Yet other changes suggest the involvement of pathways that quiescent cells might utilize to protect themselves against senescence or differentiation. It has been hypothesized that these same pathways might be ‘co-opted’ by tumor cells to allow them to maintain their proliferative potential and avoid terminal cell fates [12].

The HES1 transcriptional repressor has been identified as one of the genes that might protect quiescent cells from a differentiated fate. Some tumor cells also rely on HES1 for protection against differentiation. Here we consider several pathways that activate HES1—the Notch and Hedgehog pathways—and an effector pathway of HES1—HDACs. Small molecule regulators of each of these pathways have shown promise as anticancer drugs and are being developed in clinical trials, as summarized in Table 1. We will show how these compounds, individually and in combination, might represent promising avenues for the treatment of multiple tumor types.