Abstract:Changes in cellular gene expression in response to small-molecule or genetic perturbations have yielded signatures that can connect unknown mechanisms of action (MoA) to ones previously established. We hypothesized that differential basal gene expression could be correlated with patterns of small-molecule sensitivity across many cell lines to illuminate the actions of compounds whose MoA are unknown. To test this idea, we correlated the sensitivity patterns of 481 compounds with ~19,000 basal transcript levels… Show more
“…To account for these differences and determine where treatment with HDACi may be beneficial, diagnostic indicators of HDACi efficacy are needed. While several genomic approaches correlating HDACi response with mutational landscape or changes in basal gene expression serve as invaluable tools to identify prognostic markers associated with HDACi efficacy (Rees et al, 2016, Garnett et al, 2012), our study compliments this approach by identifying direct changes in HDAC binding, selectivity and enzymatic activity, which may also affect HDACi efficacy.…”
Summary
Histone deacetylase (HDAC) catalytic activity is regulated by formation of co-regulator complexes and post-translational modification. Whether these mechanisms are transformed in cancer and how this affects the binding and selectivity of HDAC inhibitors (HDACi) is unclear. In this study, we developed a method that identified a 3-16-fold increase in HDACi selectivity for HDAC3 in triple negative breast cancer cells (TNBC) in comparison to luminal subtypes that was not predicted by current practice measurements with recombinant proteins. We found this increase was caused by c-Jun N-terminal kinase (JNK) phosphorylation of HDAC3, was independent of HDAC3 complex composition or subcellular localization, and was associated with a 5-fold increase in HDAC3 enzymatic activity. This study points to HDAC3 and the JNK axes as targets in TNBC, highlights how HDAC phosphorylation affects HDACi binding and selectivity, and outlines a method to identify changes in individual HDAC isoforms catalytic activity, applicable to any disease state.
“…To account for these differences and determine where treatment with HDACi may be beneficial, diagnostic indicators of HDACi efficacy are needed. While several genomic approaches correlating HDACi response with mutational landscape or changes in basal gene expression serve as invaluable tools to identify prognostic markers associated with HDACi efficacy (Rees et al, 2016, Garnett et al, 2012), our study compliments this approach by identifying direct changes in HDAC binding, selectivity and enzymatic activity, which may also affect HDACi efficacy.…”
Summary
Histone deacetylase (HDAC) catalytic activity is regulated by formation of co-regulator complexes and post-translational modification. Whether these mechanisms are transformed in cancer and how this affects the binding and selectivity of HDAC inhibitors (HDACi) is unclear. In this study, we developed a method that identified a 3-16-fold increase in HDACi selectivity for HDAC3 in triple negative breast cancer cells (TNBC) in comparison to luminal subtypes that was not predicted by current practice measurements with recombinant proteins. We found this increase was caused by c-Jun N-terminal kinase (JNK) phosphorylation of HDAC3, was independent of HDAC3 complex composition or subcellular localization, and was associated with a 5-fold increase in HDAC3 enzymatic activity. This study points to HDAC3 and the JNK axes as targets in TNBC, highlights how HDAC phosphorylation affects HDACi binding and selectivity, and outlines a method to identify changes in individual HDAC isoforms catalytic activity, applicable to any disease state.
“…[27] Looking at gene expression profiles of breast cancer cells treated with ML239, NF-kB (nuclear factor kappa-light-chainenhancer of activated B cells), a protein complex that is implicated in transcription and cytokine production, was significantly altered. [28] It was subsequently argued that ML239 acts mainly through activation of FADS2 (fatty acid desaturase 2), [29] supporting the notion that metabolic states of CSCs can potentially be exploited for therapeutic purposes. Other classes of molecules, such as cinnamides, [15b] were also identified to target CSCs using the HMLER model, highlighting the power of unbiased approaches in the context of CSCs where little is known about a potential Achilles' heel.…”
Cancers arise as a result of physiological imbalances and subsequent uncontrolled cell division. Cancer initiation requires a set of biochemical alterations, including some occurring at the genetic and epigenetic levels. Thus, tumors are heterogeneous in nature making it challenging to selectively target different cancer cells by means of small molecule intervention. The paradigm of cancer stem cells (CSCs) describes subpopulations of cells with high selfrenewal and tumor-seeding capacity. These cells, typically refractory to conventional therapies, can give rise to relapse after treatment. Combinatorial strategies, including drugs that selectively target this population of cells, have emerged in recent years. Here, we review how discovery-basedunbiased -screening approaches [1] have helped identify small molecules that specifically target CSCs. We also highlight biological pathways characteristic of CSCs that can potentially be selectively targeted in a hypothesis-driven manner by small molecules. We describe molecules that effectively target CSCs and emphasize what is known about their biological modes of action. The diversity and complexity of biochemical processes that CSCs may be addicted to, raises the question of how selective targeting of these pathways can be achieved. This challenge may be addressed by the continuing production of structurally complex and diverse small molecules using target and diversity-oriented synthesis approaches.[2]
“…Natural herbal products are used in traditional medicine, and it is currently considered in anticancer activities [36], [37]. These activity indexes, apoptosis stimulation and antiproliferative activities [38], as research has shown that these natural healing products had no side effects, or as minimum side effects were much more reasonable compared with that chemotherapeutic [39].…”
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