RESUMEN
The use of androgen receptor (AR) inhibitors in prostate cancer gives rise to increased cellular lineage plasticity resulting in resistance to AR-targeted therapies. In this study, we examined the chromatin landscape of AR-positive prostate cancer cells post-exposure to the AR inhibitor enzalutamide. We identified a novel regulator of cell plasticity, the homeobox transcription factor SIX2, whose motif is enriched in accessible chromatin regions after treatment. Depletion of SIX2 in androgen-independent PC-3 prostate cancer cells induced a switch from a stem-like to an epithelial state, resulting in reduced cancer-related properties such as proliferation, colony formation, and metastasis both in vitro and in vivo. These effects were mediated through the downregulation of the Wnt/ß-catenin signalling pathway and subsequent reduction of nuclear ß-catenin. Collectively, our findings provide compelling evidence that the depletion of SIX2 may represent a promising strategy for overcoming the cell plasticity mechanisms driving antiandrogen resistance in prostate cancer.
Asunto(s)
Benzamidas , Plasticidad de la Célula , Proteínas de Homeodominio , Nitrilos , Feniltiohidantoína , Neoplasias de la Próstata , Receptores Androgénicos , Vía de Señalización Wnt , beta Catenina , Animales , Humanos , Masculino , Ratones , Benzamidas/farmacología , beta Catenina/metabolismo , beta Catenina/genética , Línea Celular Tumoral , Plasticidad de la Célula/genética , Proliferación Celular/efectos de los fármacos , Resistencia a Antineoplásicos/genética , Regulación Neoplásica de la Expresión Génica , Proteínas de Homeodominio/metabolismo , Proteínas de Homeodominio/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Nitrilos/farmacología , Células PC-3 , Feniltiohidantoína/farmacología , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/metabolismo , Receptores Androgénicos/genética , Vía de Señalización Wnt/efectos de los fármacosRESUMEN
Prostate cancer is one of the leading causes of death among men worldwide, and thus, research on the genetic factors enabling the formation of treatment-resistant cancer cells is crucial for improving patient outcomes. Here, we report a cell line-specific dependence on FANCI and related signaling pathways to counteract the effects of DNA-damaging chemotherapy in prostate cancer. Our results reveal that FANCI depletion results in significant downregulation of Fanconi anemia (FA) pathway members in prostate cancer cells, indicating that FANCI is an important regulator of the FA pathway. Furthermore, we found that FANCI silencing reduces proliferation in p53-expressing prostate cancer cells. This extends the evidence that inactivation of FANCI may convert cancer cells from a resistant state to an eradicable state under the stress of DNA-damaging chemotherapy. Our results also indicate that high expression of FA pathway genes correlates with poorer survival in prostate cancer patients. Moreover, genomic alterations of FA pathway members are prevalent in prostate adenocarcinoma patients; mutation and copy number information for the FA pathway genes in seven patient cohorts (N = 1,732 total tumor samples) reveals that 1,025 (59.2%) tumor samples have an alteration in at least one of the FA pathway genes, suggesting that genomic alteration of the pathway is a prominent feature in patients with the disease.