RESUMO
The lysine methyltransferase SETD6 modifies the histone variant H2AZ, a key component of nuclear receptor-dependent transcription. Herein, we report the identification of several factors that associate with SETD6 and are implicated in nuclear hormone receptor signaling. Specifically, SETD6 associates with the estrogen receptor α (ERα), histone deacetylase HDAC1, metastasis protein MTA2, and the transcriptional co-activator TRRAP. Luciferase reporter assays identify SETD6 as a transcriptional repressor, in agreement with its association with HDAC1 and MTA2. However, SETD6 behaves as a co-activator of several estrogen-responsive genes, such as PGR and TFF1. Consistent with these results, silencing of SETD6 in several breast carcinoma cell lines induced cellular proliferation defects accompanied by enhanced expression of the cell cycle inhibitor CDKN1A and induction of apoptosis. Herein, we have identified several chromatin proteins that associate with SETD6 and described SETD6 as an essential factor for nuclear receptor signaling and cellular proliferation.
Assuntos
Neoplasias da Mama/genética , Proliferação de Células , Estrogênios/metabolismo , Proteínas Nucleares/genética , Proteínas Metiltransferases/metabolismo , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular , Linhagem Celular Tumoral , Cromatina/genética , Cromatina/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Humanos , Proteínas Nucleares/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Transdução de Sinais , Transcrição GênicaRESUMO
Castration resistant prostate cancer remains a major clinical burden and novel therapeutic options are urgently required to improve survival. Tasquinimod is an orally administered quinoline-3-carboxamide with potent antiangiogenic and antitumorigenic action that has shown promise in the treatment of advanced prostate cancers. This review explores both preclinical and clinical findings to date. In summary, tasquinimod has been shown to demonstrate a potent in vitro and in vivo anticancer action and completed early phase clinical trials have demonstrated good drug tolerance and prolonged progression-free survival. Although Phase III clinical trials are on-going, the findings to date highlight the promise of this drug in the treatment of advanced prostate cancer.