Synthetic trimethyllysine receptors that bind histone 3, trimethyllysine 27 (H3K27me3) and disrupt its interaction with the epigenetic reader protein CBX7

Tabet, Sara; Douglas, Sarah F.; Daze, Kevin D.; Garnett, Graham A. E.; Allen, Kevin; Abrioux, Emma M.M.; Quon, Taylor T. H.; Wulff, Jeremy E.; Hof, Fraser

doi:10.1016/j.bmc.2013.09.024

Cited by 37 publications

(20 citation statements)

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“…The inference is corroborated by further experiments. Over expression of Cbx7 resulted in much less demethylated FasL gene promoter DNA; the underlying mechanism may be that Cbx7 promotes the methylation of FasL promoter since Cbx7 is an epigenetic reader protein and is capable of modulating the epigenetic activities [25]. Cbx7 is inversely associated with the expression of Cdkn2a (Ink4a; cyclin-dependent kinase inhibitor), and thus with the prognosis of certain cancers [26].…”

Section: Discussionmentioning

confidence: 99%

Polycomb chromobox (Cbx) 7 modulates activation-induced CD4+ T cell apoptosis

Li¹,

Li²,

Cao³

et al. 2014

Archives of Biochemistry and Biophysics

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Section: Discussionmentioning

confidence: 99%

Polycomb chromobox (Cbx) 7 modulates activation-induced CD4+ T cell apoptosis

Li¹,

Li²,

Cao³

et al. 2014

Archives of Biochemistry and Biophysics

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“…We report aberrant regulation of CBX2 in the breast, lung, colorectal, prostate, brain, and haematopoietic tumours, all of which rank among the 10 deadliest neoplastic diseases worldwide and are in dire need of novel therapeutics. Furthermore, epigenetic alterations are reversible and recent studies have highlighted the possibility of targeting histone readers with small-molecule inhibitors ( Dawson et al , 2012 ; Tabet et al , 2013 ). Taken together, our work has identified a putative oncogenic role for CBX2 in numerous tumour types and has provided the rationale for the design of novel CBX2-targeting therapies.…”

Section: Discussionmentioning

confidence: 99%

Genotranscriptomic meta-analysis of the Polycomb gene CBX2 in human cancers: initial evidence of an oncogenic role

Sun

Crea

et al. 2014

Br J Cancer

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Background:Polycomb group (PcG) proteins are histone modifiers known to transcriptionally silence key tumour suppressor genes in multiple human cancers. The chromobox proteins (CBX2, 4, 6, 7, and 8) are critical components of PcG-mediated repression. Four of them have been associated with tumour biology, but the role of CBX2 in cancer remains largely uncharacterised.Methods:Addressing this issue, we conducted a comprehensive and unbiased genotranscriptomic meta-analysis of CBX2 in human cancers using the COSMIC and Oncomine databases.Results:We discovered changes in gene expression that are suggestive of a widespread oncogenic role for CBX2. Our genetic analysis of 8013 tumours spanning 29 tissue types revealed no inactivating chromosomal aberrations and only 40 point mutations at the CBX2 locus. In contrast, the overall rate of CBX2 amplification averaged 10% in all combined neoplasms but exceeded 30% in ovarian, breast, and lung tumours. In addition, transcriptomic analyses revealed a strong tendency for increased CBX2 mRNA levels in many cancers compared with normal tissues, independently of CDKN2A/B silencing. Furthermore, CBX2 upregulation and amplification significantly correlated with metastatic progression and lower overall survival in many cancer types, particularly those of the breast.Conclusions:Overall, we report that the molecular profile of CBX2 is suggestive of an oncogenic role. As CBX2 has never been studied in human neoplasms, our results provide the rationale to further investigate the function of CBX2 in the context of cancer cells.

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“…Such small molecules could be used to fine-tune a balance between stem cell self-renewal and differentiation, and also be developed into potential new therapeutics for cancer treatment. Despite the functional importance of CBX7 in gene regulation, only recently have macrocyclic calixarenes (Tabet et al, 2013) and peptidomimetics (Simhadri et al, 2014) been shown as CBX7ChD antagonists, but no small-molecule chemical inhibitors have been reported for CBX7ChD or other CBX ChDs. Here, we report discovery and characterization of small molecule chemical modulators of the CBX7ChD, and demonstrate that a lead compound, MS37452, induces transcriptional de-repression of p16/CDKN2A by disrupting CBX7ChD binding to H3K27me3 at the INK4A/ARF locus in PC3 prostate cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain

Ren

Morohashi

Plotnikov

et al. 2015

Chemistry & Biology

109

101

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SUMMARY Chromobox homolog 7 (CBX7) plays an important role in gene transcription in a wide array of cellular processes, ranging from stem cell self-renewal and differentiation to tumor progression. CBX7 functions through its N-terminal chromodomain (ChD), which recognizes tri-methylated lysine 27 of histone 3 (H3K27me3), a conserved epigenetic mark that signifies gene transcriptional repression. In this study, we report discovery of small molecules that inhibit CBX7ChD binding to H3K27me3. Our crystal structures reveal the binding modes of these molecules that compete against H3K27me3 binding through interactions with key residues in the methyl-lysine binding pocket of CBX7ChD. We further show that a lead compound MS37452, de-represses transcription of Polycomb repressive complex target gene p16/CDKN2A by displacing CBX7 binding to the INK4A/ARF locus in prostate cancer cells. These small molecules have the potential to be developed into high-potency chemical modulators that target CBX7 functions in gene transcription in different disease pathways.

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Synthetic trimethyllysine receptors that bind histone 3, trimethyllysine 27 (H3K27me3) and disrupt its interaction with the epigenetic reader protein CBX7

Cited by 37 publications

References 50 publications

Polycomb chromobox (Cbx) 7 modulates activation-induced CD4+ T cell apoptosis

Polycomb chromobox (Cbx) 7 modulates activation-induced CD4+ T cell apoptosis

Genotranscriptomic meta-analysis of the Polycomb gene CBX2 in human cancers: initial evidence of an oncogenic role

Small-Molecule Modulators of Methyl-Lysine Binding for the CBX7 Chromodomain

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