Targeting Epigenetic ‘Readers’ with Natural Compounds for Cancer Interception

Damiani, Elisabetta; Duran, Munevver; Mohan, Nivedhitha; Rajendran, Praveen; Dashwood, Roderick H.

doi:10.15430/jcp.2020.25.4.189

Cited by 13 publications

(8 citation statements)

References 142 publications

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“…This could be a pertinent consideration in future studies that assess epigenetic combinations in the context of chemosensitization to platinum-based therapy [24]. Finally, a future goal will be the identification of PROTAClike bioactives from natural sources, as lead molecules that preferentially target HDAC3 and/or BRD4 for protein degradation, thereby enhancing chemosensitization in clinical trials [27].…”

Section: Discussionmentioning

confidence: 99%

Deacetylase Plus Bromodomain Inhibition Downregulates ERCC2 and Suppresses the Growth of Metastatic Colon Cancer Cells

Kapoor

Gustafson

Zhang

et al. 2021

Cancers

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There is growing evidence that DNA repair factors have clinical value for cancer treatment. Nucleotide excision repair (NER) proteins, including excision repair cross-complementation group 2 (ERCC2), play a critical role in maintaining genome integrity. Here, we examined ERCC2 expression following epigenetic combination drug treatment. Attention was drawn to ERCC2 for three reasons. First, from online databases, colorectal cancer (CRC) patients exhibited significantly reduced survival when ERCC2 was overexpressed in colon tumors. Second, ERCC2 was the most highly downregulated RNA transcript in human colon cancer cells and rat tumors after treatment with the histone deacetylase 3 (HDAC3) inhibitor sulforaphane (SFN) plus JQ1, which is an inhibitor of the bromodomain and extraterminal domain (BET) family. Third, as reported here, RNA-sequencing of polyposis in rat colon (Pirc) polyps following treatment of rats with JQ1 plus 6-methylsulfinylhexyl isothiocyanate (6-SFN) identified Ercc2 as the most highly downregulated gene. The current work also defined promising second-generation epigenetic drug combinations with enhanced synergy and efficacy, especially in metastasis-lineage colon cancer cells cultured as 3D spheroids and xenografts. This investigation adds to the growing interest in combination approaches that target epigenetic ‘readers’, ‘writers’, and ‘erasers’ that are deregulated in cancer and other pathologies, providing new avenues for precision oncology and cancer interception.

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Section: Discussionmentioning

confidence: 99%

Deacetylase Plus Bromodomain Inhibition Downregulates ERCC2 and Suppresses the Growth of Metastatic Colon Cancer Cells

Kapoor

Gustafson

Zhang

et al. 2021

Cancers

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“…Dietary factors provide many new opportunities to develop new chemopreventive agents with potent anticancer activities [12]. In this sense, dietary compounds may also serve as a pharmacological core for new drugs to reprogram cancer cells to "normal" differentiation features and regulate gene expression by targeting the cancer epigenetic dysregulation [144][145][146][147]. Currently, due to the rich source of active dietary compounds, the pursuit of new, more specific, and more potent HDAC inhibitors has moved towards dietary factors; this aims to identify novel drugs with HDACs inhibition activities for cancer treatment and other epigenetic dysbalance-associated diseases, such as fragile X syndrome and autoimmune disorders [148][149][150].…”

Section: Natural Compounds In Targeting Histone Deacetylases For Canc...mentioning

confidence: 99%

Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention

et al. 2022

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The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.

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“…domains that can recognise and bind various covalent modifications found on DNA and histones, many chromatin modifiers operate as epigenetic erasers [116]. For the sake of brevity, in what follows only protein domains that can detect and bind to methylated DNA and those domains that can recognise and bind to the two commonly studied histone modifications, acetylation and methylation [98] will be discussed.…”

Section: Epigenetic Erasersmentioning

confidence: 99%