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

Abstract

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.

Figure 1. Comparison of different cellular fates

Most cells within our body normally commit to one of five distinct cell fates: they can remain in the cell cycle and continue proliferation, or exit the cell cycle and become quiescent, senescent, differentiated or apoptotic. Quiescence is a reversible non-dividing state from which cells can be stimulated to proliferate in response to physiological signals. Senescence, differentiation, and apoptosis are all irreversible, terminal states. Senescence is a state of permanent cell-cycle arrest that can result from dysfunctional telomeres or stress. Differentiation represents the commitment to a lineage-specific cell type, such as muscle and neuron. Apoptosis is the process of programmed cell death. In contrast to normal cells, cancer cells are hyper-proliferative. They can escape senescence or apoptosis, and are poorly differentiated in many cases. A subpopulation of cells within a tumor, the cancer stem cells or dormant cancer cells, have been reported to exist in a quiescent state and thus to be responsible for the continued self-renewal capacity of the tumor.

Figure 2. Role of HES1 in quiescence and cancer

HES1 usually functions to inhibit differentiation in normal cells and tumors. HES1 is induced in quiescent cells, possibly through signaling from the notch pathway, the JNK pathway or other pathways. In cancer cells, HES1 upregulation likely occurs via the notch pathway or the hedgehog pathway. Small molecule inhibitors of the notch and hedgehog pathways have shown promise as anti-cancer agents possibly in part due to their effects on HES1. HES1 functions as a transcriptional repressor by interacting with histone deacetylases including HDAC1. HDACi’s have many cellular effects, including inhibition of HDAC1 activity and might thereby repress the effects of HES1. Agents that directly induce differentiation can also be effective as anti-cancer agents. Further, combinations of these agents can often be even more effective than the agents individually, possibly due to regulation of different sets of targets or a stronger regulation of key target genes.