Similar Datasets
Project description:Histone H3 lysine 27 to methionine mutations (H3K27M) resulting in aberrant chromatin regulation are frequently observed in Diffuse Intrinsic Pontine Glioma (DIPG), a pediatric brain tumor with no cure. We conducted a CRISPR screen to determine if various chromatin regulators might be targeted to treat DIPG. Excitingly, this genetic screen reveals that co-targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) results in an enhanced growth suppressive effect in patient DIPG cells. Consistent with the genetic screen, a bifunctional inhibitor of HDACs and LSD1, Corin, inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin rescues H3K27me3 levels typically suppressed by the dominant effects of H3K27M mutations in DIPG and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at enhancers. Further studies reveal that Corin de-regulates DIPG transcription resulting in cell death, cell cycle arrest, and the induction of neuronal differentiation. These data suggest that co-targeting LSD1 and HDACs may represent a novel strategy for treating DIPG.
2019-09-26 | GSE110571 | GEO
Project description:Histone H3 lysine 27 to methionine mutations (H3K27M) resulting in aberrant chromatin regulation are frequently observed in Diffuse Intrinsic Pontine Glioma (DIPG), a pediatric brain tumor with no cure. We conducted a CRISPR screen to determine if various chromatin regulators might be targeted to treat DIPG. Excitingly, this genetic screen reveals that co-targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDACs) results in an enhanced growth suppressive effect in patient DIPG cells. Consistent with the genetic screen, a bifunctional inhibitor of HDACs and LSD1, Corin, inhibits DIPG growth in vitro and in xenografts. Mechanistically, Corin rescues H3K27me3 levels typically suppressed by the dominant effects of H3K27M mutations in DIPG and simultaneously increases HDAC-targeted H3K27ac and LSD1-targeted H3K4me1 at enhancers. Further studies reveal that Corin de-regulates DIPG transcription resulting in cell death, cell cycle arrest, and the induction of neuronal differentiation. These data suggest that co-targeting LSD1 and HDACs may represent a novel strategy for treating DIPG.
2019-09-25 | GSE110570 | GEO
Project description:Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG
| PRJNA434015 | ENA
Project description:Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG [ChIP-seq]
| PRJNA434043 | ENA
Project description:Re-programing chromatin with a bifunctional LSD1/HDAC inhibitor induces therapeutic differentiation in DIPG [RNA-seq]
| PRJNA434042 | ENA
Project description:The lysine-specific demethylase 1 (LSD1) is overexpressed in several cancers including rhabdomyosarcoma (RMS). However, little is yet known about whether or not LSD1 may serve as therapeutic target in RMS. We therefore investigated the potential of LSD1 inhibitors alone or in combination with other epigenetic modifiers such as histone deacetylase (HDAC) inhibitors. Here, we identify a synergistic interaction of LSD1 inhibitors (i.e., GSK690, Ex917) and HDAC inhibitors (i.e., JNJ-26481585, SAHA) to induce cell death in RMS cells. By comparison, LSD1 inhibitors as single agents exhibit little cytotoxicity against RMS cells. Mechanistically, GSK690 acts in concert with JNJ-26481585 to upregulate mRNA levels of the proapoptotic BH3-only proteins BMF, PUMA, BIM and NOXA. This increase in mRNA levels is accompanied by a corresponding upregulation of BMF, PUMA, BIM and NOXA protein levels. Importantly, individual knockdown of either BMF, BIM or NOXA significantly reduces GSK690/JNJ-26481585-mediated cell death. Similarly, genetic silencing of BAK significantly rescues cell death upon GSK690/JNJ-26481585 cotreatment. Also, overexpression of antiapoptotic BCL-2 or MCL-1 significantly protects RMS cells from GSK690/JNJ-26481585-induced cell death. Furthermore, GSK690 acts in concert with JNJ-26481585 to increase activation of caspase-9 and -3. Consistently, addition of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD.fmk) significantly reduces GSK690/JNJ-26481585-mediated cell death. In conclusion, concomitant LSD1 and HDAC inhibition synergistically induces cell death in RMS cells by shifting the ratio of pro- and antiapoptotic BCL-2 proteins in favor of apoptosis, thereby engaging the intrinsic apoptotic pathway. This indicates that combined treatment with LSD1 and HDAC inhibitors is a promising new therapeutic approach in RMS.
| S-EPMC5520898 | biostudies-other
Project description:Plants are known to respond to Ultraviolet-B radiation (UV-B: 280-320 nm) by generating phenolic metabolites which absorbs UV-B light. Phenolics are extraordinarily abundant in Camellia sinensis leaves and are considered, together with pleasant volatile terpenoids, as primary flavor determinants in tea beverages. In this study, we focused on the effects of UV-B exposure (at 35 ?W cm-2 for 0, 0.5, 2, and 8 h) on tea transcriptional and metabolic alterations, specifically related to tea flavor metabolite production. Out of 34,737 unigenes, a total of 18,081 differentially expressed genes (DEGs) due to UV-B treatments were identified. Additionally, the phenylpropanoid pathway was found as one of the most significantly UV-B affected top 20 KEGG pathways while flavonoid and monoterpenoid pathway-related genes were enhanced at 0.5 h. In the UVR8-signal transduction pathway, UVR8 was suppressed at both short and long exposure of UV-B with genes downstream differentially expressed. Divergent expression of MYB4 at different treatments could have differentially altered structural and regulatory genes upstream of flavonoid biosynthesis pathways. Suppression of MYB4-1&3 at 0.5 h could have led to the up-regulation of structural CCOAOMT-1&2, HST-1&2, DFR-4, ANR-2, and LAR-1&3 genes resulting in accumulation of specialized metabolites at a shorter duration of UV-B exposure. Specialized metabolite profiling revealed the correlated alterations in the abundances of catechins and some volatile terpenoids in all the treatments with significant accumulation of specialized metabolites at 0.5 h treatment. A significant increase in specialized metabolites at 0.5 h treatment and no significant alteration observed at longer UVB treatment suggested that shorter exposure to UV-B led to different display in gene expression and accumulation of specialized metabolites in tea shoots in response to UV-B stress. Taken together, our results indicated that the UV-B treatment applied in this study differentially altered the UVR8-signal transduction, flavonoid and terpenoid pathways at transcriptional and metabolic levels in tea plants. Our results show strong potential for UV-B application in flavor improvement in tea at the industrial level.
| S-EPMC7062797 | biostudies-literature
Project description:Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1-CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for maintaining cellular plasticity and proliferation in MCC. There is growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.
| S-SCDT-EMM-2020-12525 | biostudies-other
Project description:Our recent studies have shown that cross-talk between histone deacetylase 5 (HDAC5) and lysine-specific demethylase 1 (LSD1) facilitates breast cancer progression. In this work, we demonstrated that regulatory activity at -356 to -100 bp promoter element plays a critical role in governing HDAC5 transcription. By using DNA affinity precipitation and mass spectrometry, we identified a group of factors that bind to this element. Among these factors, Upstream Transcription Factor 1 (USF1) was shown to play a critical role in controlling HDAC5 transcription. Through screening a panel of epigenetic modifying drugs, we showed that a natural bioactive HDAC inhibitor, sulforaphane, downregulated HDAC5 transcription by blocking USF1 activity. Sulforaphane facilitated LSD1 ubiquitination and degradation in an HDAC5-dependent manner. A comparative microarray analysis demonstrated a genome wide cooperative effect of HDAC5 and LSD1 on cancer-related gene expression. shRNA knockdown and sulforaphane inhibition of HDAC5/LSD1 exhibited similar effects on expression of HDAC5/LSD1 target genes. We also showed that coordinated cross-talk of HDAC5 and LSD1 is essential for the antitumor efficacy of sulforaphane. Combination treatment with sulforaphane and a potent LSD1 inhibitor resulted in synergistic growth inhibition in breast cancer cells, but not in normal breast epithelial cells. Furthermore, combined therapy with sulforaphane and LSD1 inhibitor exhibited superior inhibitory effect on MDA-MB-231 xenograft tumor growth. Taken together, our work demonstrates that HDAC5-LSD1 axis is an effective drug target for breast cancer. Inhibition of HDAC5-LSD1 axis with sulforaphane blocks breast cancer growth and combined treatment with LSD1 inhibitor improves the therapeutic efficacy of sulforaphane.
| S-EPMC6105499 | biostudies-literature
Project description:Merkel cell carcinoma (MCC) is a highly aggressive, neuroendocrine skin cancer that lacks actionable mutations, which could be utilized for targeted therapies. Epigenetic regulators governing cell identity may represent unexplored therapeutic entry points. Here, we targeted epigenetic regulators in a pharmacological screen and discovered that the lysine-specific histone demethylase 1A (LSD1/KDM1A) is required for MCC growth in vitro and in vivo. We show that LSD1 inhibition in MCC disrupts the LSD1-CoREST complex leading to displacement and degradation of HMG20B (BRAF35), a poorly characterized complex member that is essential for MCC proliferation. Inhibition of LSD1 causes derepression of transcriptional master regulators of the neuronal lineage, activates a gene expression signature resembling normal Merkel cells, and induces cell cycle arrest and cell death. Our study unveils the importance of LSD1 for maintaining cellular plasticity and proliferation in MCC. There is also growing evidence that cancer cells exploit cellular plasticity and dedifferentiation programs to evade destruction by the immune system. The combination of LSD1 inhibitors with checkpoint inhibitors may thus represent a promising treatment strategy for MCC patients.
| S-EPMC7645387 | biostudies-literature