RESUMEN
Upregulation of histone methyltransferase SET domain bifurcated 1 (SETDB1) is associated with poor prognosis in cancer patients. However, the mechanism of oncogenicity of SETDB1 in cancer is hitherto unknown. Here, we show that SETDB1 is upregulated in human colorectal cancer (CRC) where its level correlates with poor clinical outcome. Ectopic SETDB1 promotes CRC cell proliferation, whereas SETDB1 attenuation inhibits this process. Flow cytometry reveals that SETDB1 promotes proliferation by driving the CRC cell cycle from G0/G1 phase to S phase. Mechanistically, SETDB1 binds directly to the STAT1 promoter region resulting in increased STAT1 expression. Functional characterization reveals that STAT1-CCND1/CDK6 axis is a downstream effector of SETDB1-mediated CRC cell proliferation. Furthermore, SETDB1 upregulation is sufficient to accelerate in vivo proliferation in xenograft animal model. Taken together, our results provide insight into the upregulation of SETDB1 within CRC and can lead to novel treatment strategies targeting this cell proliferation-promoting gene.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Proliferación Celular , Neoplasias Colorrectales/patología , Ciclina D1/metabolismo , Quinasa 6 Dependiente de la Ciclina/metabolismo , N-Metiltransferasa de Histona-Lisina/metabolismo , Factor de Transcripción STAT1/metabolismo , Animales , Apoptosis , Biomarcadores de Tumor/genética , Movimiento Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Ciclina D1/genética , Quinasa 6 Dependiente de la Ciclina/genética , Regulación Neoplásica de la Expresión Génica , N-Metiltransferasa de Histona-Lisina/genética , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Factor de Transcripción STAT1/genética , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
In order to develop NIR BODIPY for mitochondria targeting imaging agents and metal sensors, a side chain modified BODIPY (BPN) was synthesized and spectroscopically characterized. BPN has NIR emission at 765nm when excited at 704nm. The emission at 765nm responded differently to Cu2+ and Mn2+ ions, respectively. The BPN coordinated with Cu2+ forming [BPNCu]2+ complex with quenched emission, while Mn2+ induced aggregation of BPN with specific fluorescence enhancement. Moreover, BPN can be applied to monitor Cu2+ in live cells and image mitochondria. Further, BPN was used as sensor for the detection of Cu2+ ions in serum with linear detection range of 0.45µM-36.30µM. Results indicate that BPN is a good sensor for the detection of Cu2+ in serum and image mitochondria. This study gives strategies for future design of NIR sensors for the analysis of metal ions in blood.