To date, it remains poorly understood whether astrocytes can be easily reprogrammed into neurons. Mashl and Brn2 have been previously shown to cooperate to reprogram fibroblasts into neurons. In this study, we examine...To date, it remains poorly understood whether astrocytes can be easily reprogrammed into neurons. Mashl and Brn2 have been previously shown to cooperate to reprogram fibroblasts into neurons. In this study, we examined astrocytes from 2-month-old Sprague-Dawley rats, and found that Brn2 was expressed, but Mashl was not detectable. Thus, we hypothesized that Mashl alone could be used to reprogram astrocytes into neurons. We transfected a recombinant MSCV-MASH1 plasmid into astrocytes for 72 hours, and saw that all cells expressed Mashl. One week later, we observed the changes in morphology of astrocytes, which showed typical neuro- nal characteristics. Moreover, β-tubulin expression levels were significantly higher in astrocytes expressing Mashl than in control cells. These results indicate that Mashl alone can reprogram astrocytes into neurons.展开更多
Tumor lineage plasticity(LP)is an emerging hallmark of cancer progression.Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids,we identified bromodomain protei...Tumor lineage plasticity(LP)is an emerging hallmark of cancer progression.Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids,we identified bromodomain protein BRD4 as a crucial player.Integrated ChIP-seq and RNA-seq analysis of tumors revealed,for the first time,that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis,axonogenesis,EMT and stem cells and key drivers such as POU3F2(BRN2),ASCL1/2,NeuroD1,SOX2/9,RUNX1/2 and DLL3.Interestingly,BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1.Significantly,we demonstrated that BRD4 inhibitor AZD5153,currently at clinical development,possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer(NEPC)and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action(MOA)by AZD5153.Together,our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.展开更多
基金supported by the National Basic Research Program of China(973 Program),No.2010CB530400the Key Project of National Natural Science Foundation of China,No.30930111
文摘To date, it remains poorly understood whether astrocytes can be easily reprogrammed into neurons. Mashl and Brn2 have been previously shown to cooperate to reprogram fibroblasts into neurons. In this study, we examined astrocytes from 2-month-old Sprague-Dawley rats, and found that Brn2 was expressed, but Mashl was not detectable. Thus, we hypothesized that Mashl alone could be used to reprogram astrocytes into neurons. We transfected a recombinant MSCV-MASH1 plasmid into astrocytes for 72 hours, and saw that all cells expressed Mashl. One week later, we observed the changes in morphology of astrocytes, which showed typical neuro- nal characteristics. Moreover, β-tubulin expression levels were significantly higher in astrocytes expressing Mashl than in control cells. These results indicate that Mashl alone can reprogram astrocytes into neurons.
基金supported in part by grants from the NIH(R01 CA259081 and R01 CA224900,USA)the Prostate Cancer Foundation(16CHAL02,USA),the US Department of DefensePCRP(PC200522,USA)+1 种基金the US Department of Veterans Affairs,Office of Research and Development BL&D(I01 BX004271,USA)H-WC.The UCDCCC GSR is supported by the NCI Cancer Center Support Grant(NCI P30CA093373,USA).
文摘Tumor lineage plasticity(LP)is an emerging hallmark of cancer progression.Through pharmacologically probing the function of epigenetic regulators in prostate cancer cells and organoids,we identified bromodomain protein BRD4 as a crucial player.Integrated ChIP-seq and RNA-seq analysis of tumors revealed,for the first time,that BRD4 directly activates hundreds of genes in the LP programs which include neurogenesis,axonogenesis,EMT and stem cells and key drivers such as POU3F2(BRN2),ASCL1/2,NeuroD1,SOX2/9,RUNX1/2 and DLL3.Interestingly,BRD4 genome occupancy is reprogrammed by anti-AR drugs from facilitating AR function in CRPC cells to activating the LP programs and is facilitated by pioneer factor FOXA1.Significantly,we demonstrated that BRD4 inhibitor AZD5153,currently at clinical development,possesses potent activities in complete blockade of tumor growth of both de novo neuroendocrine prostate cancer(NEPC)and treatment-induced NEPC PDXs and that suppression of tumor expression of LP programs through reduction of local chromatin accessibility is the primary mechanism of action(MOA)by AZD5153.Together,our study revealed that BRD4 plays a fundamental role in direct activation of tumor LP programs and that its inhibitor AZD5153 is highly promising in effective treatment of the lethal forms of the diseases.
