Article

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

ABSTRACT

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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    • "Oncogenic transcriptional rigidity reflects the simultane‐ ous deregulation of target loci such that proliferative and survival signals are enhanced and antimitotic inputs are either limited or lost. Co-repressor proteins significantly contribute with the disruption of these processes [16]. Therefore, understanding mechanisms involved in gene regulation and transcriptional network may lead to a better knowledge about the crucial functions of TFs, providing information to explore possibilities of their application as molecular targets in cancer therapy [18]. "

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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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