Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain

James, Lindsey I.; Baršytė-Lovejoy, Dalia; Zhong, Nan; Krichevsky, Liubov; Korboukh, Victoria K.; Herold, J. Martin; MacNevin, Christopher J.; Norris, Jacqueline L.; Sagum, Cari A.; Tempel, W.; Marcon, Edyta; Guo, Hongbo; Gao, Canzhu; Huang, Xi Ping; Duan, Shili; Emili, Andrew; Greenblatt, Jack; Kireev, Dmitri; Jin, Jian; Janzen, William P.; Brown, Peter J.; Bedford, Mark T.; Arrowsmith, C.H.; Frye, Stephen V.

doi:10.1038/nchembio.1157

Cited by 159 publications

(190 citation statements)

References 49 publications

(53 reference statements)

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“…Bclaf1 may participate in the epigenetic regulation of chromatin structure as it was found to be associated with L3MBTL3, a member of the malignant brain tumor (MBT) family of chromatin-interacting transcriptional repressors. 35 Recently, Bclaf1 was identified as a component of the RNA splicing complex and regulates the stability of cyclin D and BRCA1 mRNA. 36,37 Whether this function of Bclaf1 is related to C/EBPβ upregulation requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

Sun

Geng

et al. 2016

Cell Death Differ

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Inducing senescence in cancer cells is an effective approach to suppress cancer growth, and it contributes significantly to the efficacy of therapeutic drugs. Previous studies indicated that transcription factors NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells) and C/EBPβ (CCAAT/enhancer-binding protein-β) play a critical role in the establishment of senescence by upregulating proinflammatory cytokines, notably interleukin-6 (IL-6) and interleukin-8 (IL-8). However, it is not clear how these two factors are activated in response to senescence-inducing stimuli and subsequently regulate gene transcription. Here, we reveal Bcl-2-associated transcription factor 1 (Bclaf1) as a novel player in the therapeutic drug doxorubicin-induced senescence (TIS) in multiple cancer cells. Bclaf1 is upregulated through the ATM/Nemo/NF-κB pathway during TIS and is a direct target of p65 and c-Rel. The induction of Bclaf1 by NF-κB is essential for C/EBPβ upregulation and IL-6/IL-8 transcription during TIS. Bclaf1 can interact with the leucine zipper region of C/EBPβ and cooperate with C/EBPβ to upregulate IL-8. Furthermore, we show that Bclaf1 is required for the effectiveness of doxorubicin (Dox) treatment-induced tumor suppression in a xenograft tumor model. These finding suggest that Bclaf1 plays a crucial role in transducing the senescence-inducing signal from NF-κB to C/EBPβ during TIS, thus amplifying the signals for the establishment of senescence. Given the recent revelation that Bclaf1 is involved in tumorigenesis, our data indicate that the responsiveness of Bclaf1 to NF-κB may determine the effectiveness of therapeutic drugs.

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Section: Discussionmentioning

confidence: 99%

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

Sun

Geng

et al. 2016

Cell Death Differ

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“…11 Because epigenetic changes are susceptible to pharmacologic reversion, the identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. 12,13 The use of microarrays is a common and well-validated approach for DNA-methylation profiling to identify aberrantly methylated genes and to determine new clinically relevant disease stratification. 8,14 Here we report the results of genome-wide promoter-methylation profiling of a large series of SMZL cases integrating gene expression and genetic and clinical data.…”

Section: Introductionmentioning

confidence: 99%

DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features

Arribas

Rinaldi

Mensah

et al. 2015

Blood

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Key Points• Methylation profiling identifies subgroups of SMZL with distinct biological features.• Demethylating agents can reverse some of the adverse epigenetic alterations.Splenic marginal zone lymphoma is a rare lymphoma. Loss of 7q31 and somatic mutations affecting the NOTCH2 and KLF2 genes are the commonest genomic aberrations. Epigenetic changes can be pharmacologically reverted; therefore, identification of groups of patients with specific epigenomic alterations might have therapeutic relevance. Here we integrated genome-wide DNA-promoter methylation profiling with gene expression profiling, and clinical and biological variables. An unsupervised clustering analysis of a test series of 98 samples identified 2 clusters with different degrees of promoter methylation. The cluster comprising samples with higher-promoter methylation (High-M) had a poorer overall survival compared with the lower (Low-M) cluster. The prognostic relevance of the High-M phenotype was confirmed in an independent validation set of 36 patients. In the whole series, the High-M phenotype was associated with IGHV1-02 usage, mutations of NOTCH2 gene, 7q31-32 loss, and histologic transformation. In the High-M set, a number of tumor-suppressor genes were methylated and repressed. PRC2 subunit genes and several prosurvival lymphoma genes were unmethylated and overexpressed. A model based on the methylation of 3 genes (CACNB2, HTRA1, KLF4) identified a poorer-outcome patient subset. Exposure of splenic marginal zone lymphoma cell lines to a demethylating agent caused partial reversion of the High-M phenotype and inhibition of proliferation. (Blood. 2015;125(12):1922-1931

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“…Small molecule drugs and chemical probes offer an approach to explore the biological consequences of these mutations and are emerging as a therapeutic strategy to target disease pathways. Drugs targeting histone deacetylase (HDAC) enzymes, the bromodomain reader BRD4, and DNA methylation have already received regulatory approval or have entered clinical testing, and chemical probes have been developed against a broad range of chromatin regulators, such as the methyltransferases (3) DOT1L (4), EZH2 (5)(6)(7)(8), and G9a (9,10), and the reader proteins L3MBTL3 (11) and BRD4 (12)(13)(14). However, transcription factors that lack enzymatic activity or binding pockets with targetable molecular features have been considered "undruggable," and a reductionist approach based on identification of their molecular targets has largely failed.…”

mentioning

confidence: 99%

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility

Pattenden

Simon

Wali

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Mutations in chromatin-modifying proteins and transcription factors are commonly associated with a wide variety of cancers. Through gain-or loss-of-function, these mutations may result in characteristic alterations of accessible chromatin, indicative of shifts in the landscape of regulatory elements genome-wide. The identification of compounds that reverse a specific chromatin signature could lead to chemical probes or potential therapies. To explore whether chromatin accessibility could serve as a platform for small molecule screening, we adapted formaldehyde-assisted isolation of regulatory elements (FAIRE), a chemical method to enrich for nucleosomedepleted genomic regions, as a high-throughput, automated assay. After demonstrating the validity and robustness of this approach, we applied this method to screen an epigenetically targeted small molecule library by evaluating regions of aberrant nucleosome depletion mediated by EWSR1-FLI1, the chimeric transcription factor critical for the bone and soft tissue tumor Ewing sarcoma. As a class, histone deacetylase inhibitors were greatly overrepresented among active compounds. These compounds resulted in diminished accessibility at targeted sites by disrupting transcription of EWSR1-FLI1. Capitalizing on precise differences in chromatin accessibility for drug discovery efforts offers significant advantages because it does not depend on the a priori selection of a single molecular target and may detect novel biologically relevant pathways.chromatin | Ewing sarcoma | high throughput screening | FAIRE | histone deacetylase inhibitor A growing range of human cancers have been associated with mutations in genes encoding proteins that regulate chromatin, the assembly of proteins and DNA that control DNAtemplated processes, including transcription and replication (1, 2). Small molecule drugs and chemical probes offer an approach to explore the biological consequences of these mutations and are emerging as a therapeutic strategy to target disease pathways. Drugs targeting histone deacetylase (HDAC) enzymes, the bromodomain reader BRD4, and DNA methylation have already received regulatory approval or have entered clinical testing, and chemical probes have been developed against a broad range of chromatin regulators, such as the methyltransferases (3) DOT1L (4), EZH2 (5-8), and G9a (9, 10), and the reader proteins L3MBTL3 (11) and BRD4 (12-14). However, transcription factors that lack enzymatic activity or binding pockets with targetable molecular features have been considered "undruggable," and a reductionist approach based on identification of their molecular targets has largely failed.The majority of Ewing sarcomas, highly malignant pediatric bone and soft tissue tumors, harbor a chromosomal translocation that joins the amino-terminal domain of EWSR1 with the DNA binding domain of the ETS transcription factor family member FLI1 to generate the chimeric transcription factor EWSR1-FLI1 (15). Translocations with other ETS genes are detected in most of the remaining tumors, y...

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Discovery of a chemical probe for the L3MBTL3 methyllysine reader domain

Cited by 159 publications

References 49 publications

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

Bclaf1 is an important NF-κB signaling transducer and C/EBPβ regulator in DNA damage-induced senescence

DNA methylation profiling identifies two splenic marginal zone lymphoma subgroups with different clinical and genetic features

High-throughput small molecule screen identifies inhibitors of aberrant chromatin accessibility

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