RESUMEN
Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.
Asunto(s)
Neoplasias de la Mama/metabolismo , Histona Desacetilasa 1/metabolismo , Histona Desacetilasas/metabolismo , Células Madre Neoplásicas/metabolismo , Neoplasias Ováricas/metabolismo , Animales , Biomarcadores , Neoplasias de la Mama/genética , Línea Celular Tumoral , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Femenino , Técnicas de Silenciamiento del Gen , Genes Letales , Xenoinjertos , Histona Desacetilasa 1/genética , Inhibidores de Histona Desacetilasas/farmacología , Histona Desacetilasas/genética , Humanos , Ratones , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Ováricas/genética , Fenotipo , ARN Interferente Pequeño/genéticaRESUMEN
We have isolated cDNAs encoding a second member of the dilute (myosin-V) unconventional myosin family in vertebrates, myr 6 (myosin from rat 6). Expression of myr 6 transcripts in the brain is much more limited than is the expression of dilute, with highest levels observed in choroid plexus and components of the limbic system. We have mapped the myr 6 locus to mouse chromosome 18 using an interspecific backcross. The 3' portion of the myr 6 cDNA sequence from rat is nearly identical to that of a previously published putative glutamic acid decarboxylase from mouse [Huang, W.M., Reed-Fourquet, L., Wu, E. & Wu, J.Y. (1990) Proc. Natl. Acad. Sci. USA 87, 8491-8495].
