Transcription factor co-repressors in cancer biology: Roles and targeting

Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
International Journal of Cancer (Impact Factor: 5.09). 06/2010; 126(11):2511-9. DOI: 10.1002/ijc.25181
Source: PubMed


Normal transcription displays a high degree of flexibility over the choice, timing and magnitude of mRNA expression levels that tend to oscillate and cycle. These processes allow for combinatorial actions, feedback control and fine-tuning. A central role has emerged for the transcriptional co-repressor proteins such as NCOR1, NCOR2/SMRT, CoREST and CTBPs, to control the actions of many transcriptional factors, in large part, by recruitment and activation of a range of chromatin remodeling enzymes. Thus, co-repressors and chromatin remodeling factors are recruited to transcription factors at specific promoter/enhancer regions and execute changes in the chromatin structure. The specificity of this recruitment is controlled in a spatial-temporal manner. By playing a central role in transcriptional control, as they move and target transcription factors, co-repressors act as a key driver in the epigenetic economy of the nucleus. Co-repressor functions are selectively distorted in malignancy, by both loss and gain of function and contribute to the generation of transcriptional rigidity. Features of transcriptional rigidity apparent in cancer cells include the distorted signaling of nuclear receptors and the WNTs/beta-catenin axis. Understanding and predicting the consequences of altered co-repressor expression patterns in cancer cells has diagnostic and prognostic significance, and also have the capacity to be targeted through selective epigenetic therapies.

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    • "In normal haematopoiesis , NCOR1 is a core component of the generic corepressor protein complex that interacts with un-liganded nuclear receptors and other transcription factors to mediate the repressive activity of their binding partners (Watson et al, 2012). In leukaemogenesis, the role of NCOR1 was elucidated in acute promyelocytic leukaemia and acute myeloid leukaemia (AML) through the repression of target genes related to fusion proteins, such as PML-RARA and RUNX1- RUNX1T1 (AML1-ETO) (Battaglia et al, 2010). LYN is located at 8q13 and comprises 13 exons encoding a 513 amino acid protein (NM_2350.3). "
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    ABSTRACT: Activating tyrosine kinase mutations or cytokine receptor signalling alterations have attracted attention as therapeutic targets for high-risk paediatric acute lymphoblastic leukaemia (ALL). We identified two novel kinase fusions, OFD1-JAK2 and NCOR1-LYN, in paediatric ALL patients with IKZF1 deletion, by mRNA sequencing. The patient with CSF2RA-CRLF2 also harboured IGH-EPOR. All these patients had high-risk features, such as high initial white blood cell counts and initial poor response to prednisolone. The functional analysis of these novel fusions is on-going to determine whether these genetic alterations can be targeted by drugs.
    British Journal of Haematology 09/2015; DOI:10.1111/bjh.13757 · 4.71 Impact Factor
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    • "Although CoREST acts as a corepressor in terminally differentiating nonneuronal cells by recruiting KDM1/LSD1 to demethylate H3K4me2 and the methyltransferase G9a to methylate H3K9 at the RE1 sites of target genes, it acts as a coactivator of transcription in embryonic stem cells and neural stem cells by recruiting an H3K4 methyltransferase to the RE1 sites of target genes [51]. CoREST can also form larger complexes by association with ZNF217, a Krüppel-like zinc finger protein and strong candidate oncogene product found in breast cancer, or with other complexes, such as the chromatin-remodeling complex SWI/SNF or the C-terminal binding protein (CtBP) complex [45,52]. Interestingly, CoREST appears to be involved in the negative regulation of synaptic plasticity and memory formation by HDAC2 [33]. "
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    ABSTRACT: The zinc-dependent mammalian histone deacetylase (HDAC) family comprises 11 enzymes, which have specific and critical functions in development and tissue homeostasis. Mounting evidence points to a link between misregulated HDAC activity and many oncologic and nononcologic diseases. Thus the development of HDAC inhibitors for therapeutic treatment garners a lot of interest from academic researchers and biotechnology entrepreneurs. Numerous studies of HDAC inhibitor specificities and molecular mechanisms of action are ongoing. In one of these studies, mass spectrometry was used to characterize the affinities and selectivities of HDAC inhibitors toward native HDAC multiprotein complexes in cell extracts. Such a novel approach reproduces in vivo molecular interactions more accurately than standard studies using purified proteins or protein domains as targets and could be very useful in the isolation of inhibitors with superior clinical efficacy and decreased toxicity compared to the ones presently tested or approved. HDAC inhibitor induced-transcriptional reprogramming, believed to contribute largely to their therapeutic benefits, is achieved through various and complex mechanisms not fully understood, including histone deacetylation, transcription factor or regulator (including HDAC1) deacetylation followed by chromatin remodeling and positive or negative outcome regarding transcription initiation. Although only a very low percentage of protein-coding genes are affected by the action of HDAC inhibitors, about 40% of noncoding microRNAs are upregulated or downregulated. Moreover, a whole new world of long noncoding RNAs is emerging, revealing a new class of potential targets for HDAC inhibition. HDAC inhibitors might also regulate transcription elongation and have been shown to impinge on alternative splicing.
    Clinical Epigenetics 03/2012; 4(1):5. DOI:10.1186/1868-7083-4-5 · 4.54 Impact Factor
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    • "In turn the accumulation of repressive histone modifications at suppressed target genes may allow for hypermethylation at adjacent CpG regions (28) and development of stable patterns of gene silencing [reviewed in refs. (29,30)]. "
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    ABSTRACT: In non-malignant RWPE-1 prostate epithelial cells signaling by the nuclear receptor Vitamin D Receptor (VDR, NR1I1) induces cell cycle arrest through targets including CDKN1A (encodes p21((waf1/cip1))). VDR dynamically induced individual histone modification patterns at three VDR binding sites (R1, 2, 3) on the CDKN1A promoter. The magnitude of these modifications was specific to each phase of the cell cycle. For example, H3K9ac enrichment occurred rapidly only at R2, whereas parallel accumulation of H3K27me3 occurred at R1; these events were significantly enriched in G(1) and S phase cells, respectively. The epigenetic events appeared to allow VDR actions to combine with p53 to enhance p21((waf1/cip1)) activation further. In parallel, VDR binding to the MCM7 gene induced H3K9ac enrichment associated with rapid mRNA up-regulation to generate miR-106b and consequently regulate p21((waf1/cip1)) expression. We conclude that VDR binding site- and promoter-specific patterns of histone modifications combine with miRNA co-regulation to form a VDR-regulated feed-forward loop to control p21((waf1/cip1)) expression and cell cycle arrest. Dissection of this feed-forward loop in a non-malignant prostate cell system illuminates mechanisms of sensitivity and therefore possible resistance in prostate and other VDR responsive cancers.
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