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Article ; Online: Histone Acyl Code in Precision Oncology: Mechanistic Insights from Dietary and Metabolic Factors.

Neja, Sultan / Dashwood, Wan Mohaiza / Dashwood, Roderick H / Rajendran, Praveen

2024 Volume 16, Issue 3

Abstract: Cancer etiology involves complex interactions between genetic and non-genetic factors, with epigenetic mechanisms serving as key regulators at multiple stages of pathogenesis. Poor dietary habits contribute to cancer predisposition by impacting DNA ... ...

Abstract	Cancer etiology involves complex interactions between genetic and non-genetic factors, with epigenetic mechanisms serving as key regulators at multiple stages of pathogenesis. Poor dietary habits contribute to cancer predisposition by impacting DNA methylation patterns, non-coding RNA expression, and histone epigenetic landscapes. Histone post-translational modifications (PTMs), including acyl marks, act as a molecular code and play a crucial role in translating changes in cellular metabolism into enduring patterns of gene expression. As cancer cells undergo metabolic reprogramming to support rapid growth and proliferation, nuanced roles have emerged for dietary- and metabolism-derived histone acylation changes in cancer progression. Specific types and mechanisms of histone acylation, beyond the standard acetylation marks, shed light on how dietary metabolites reshape the gut microbiome, influencing the dynamics of histone acyl repertoires. Given the reversible nature of histone PTMs, the corresponding acyl readers, writers, and erasers are discussed in this review in the context of cancer prevention and treatment. The evolving 'acyl code' provides for improved biomarker assessment and clinical validation in cancer diagnosis and prognosis.
MeSH term(s)	Humans ; Histones/metabolism ; Neoplasms/genetics ; Precision Medicine ; Histone Code ; DNA Methylation ; Protein Processing, Post-Translational ; Epigenesis, Genetic
Chemical Substances	Histones
Language	English
Publishing date	2024-01-30
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu16030396
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Cancer interception by interceptor molecules: mechanistic, preclinical and human translational studies with chlorophylls.

Dashwood, Roderick H

Genes and environment : the official journal of the Japanese Environmental Mutagen Society

2021 Volume 43, Issue 1, Page(s) 8

Abstract: Before 'cancer interception' was first advocated, 'interceptor molecules' had been conceived as a sub-category of preventive agents that interfered with the earliest initiation steps in carcinogenesis. Three decades ago, a seminal review cataloged over ... ...

Abstract	Before 'cancer interception' was first advocated, 'interceptor molecules' had been conceived as a sub-category of preventive agents that interfered with the earliest initiation steps in carcinogenesis. Three decades ago, a seminal review cataloged over fifty synthetic agents and natural products that were known or putative interceptor molecules. Chlorophylls and their derivatives garnered much interest based on the potent antimutagenic activity in the Salmonella assay, and the subsequent mechanistic work that provided proof-of-concept for direct molecular complexes with planar aromatic carcinogens. As the 'interceptor molecule' hypothesis evolved, mechanistic experiments and preclinical studies supported the view that chlorophylls can interact with environmental heterocyclic amines, aflatoxins, and polycyclic aromatic hydrocarbons to limit their uptake and bioavailability in vivo. Support also came from human translational studies involving ultralow dose detection in healthy volunteers, as well as intervention in at-risk subjects. Antimutagenic and antigenotoxic effects of natural and synthetic chlorophylls against small alkylating agents also highlighted the fact that non-interceptor mechanisms existed. This gave impetus to investigations broadly related to free radical scavenging, anti-inflammatory effects, immune modulation and photodynamic therapy. Therapeutic aspects of chlorophylls also were investigated, with evidence for cell cycle arrest and apoptosis in human cancer cells. As the science has evolved, new mechanistic leads continue to support the use and development of chlorophylls and their porphyrin derivatives for cancer interception, beyond the initial interest as interceptor molecules.
Language	English
Publishing date	2021-03-06
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2269162-5
ISSN	1880-7062 ; 1880-7046
ISSN (online)	1880-7062
ISSN	1880-7046
DOI	10.1186/s41021-021-00180-8
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Article: A-Z of Epigenetic Readers: Targeting Alternative Splicing and Histone Modification Variants in Cancer.

Mohan, Nivedhitha / Dashwood, Roderick H / Rajendran, Praveen

Cancers

2024 Volume 16, Issue 6

Abstract: Epigenetic 'reader' proteins, which have evolved to interact with specific chromatin modifications, play pivotal roles in gene regulation. There is growing interest in the alternative splicing mechanisms that affect the functionality of such epigenetic ... ...

Abstract	Epigenetic 'reader' proteins, which have evolved to interact with specific chromatin modifications, play pivotal roles in gene regulation. There is growing interest in the alternative splicing mechanisms that affect the functionality of such epigenetic readers in cancer etiology. The current review considers how deregulation of epigenetic processes and alternative splicing events contribute to pathophysiology. An A-Z guide of epigenetic readers is provided, delineating the antagonistic 'yin-yang' roles of full-length versus spliced isoforms, where this is known from the literature. The examples discussed underscore the key contributions of epigenetic readers in transcriptional regulation, early development, and cancer. Clinical implications are considered, offering insights into precision oncology and targeted therapies focused on epigenetic readers that have undergone alternative splicing events during disease pathogenesis. This review underscores the fundamental importance of alternative splicing events in the context of epigenetic readers while emphasizing the critical need for improved understanding of functional diversity, regulatory mechanisms, and future therapeutic potential.
Language	English
Publishing date	2024-03-09
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers16061104
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Article ; Online: Memories of a friend and colleague - Takashi Sugimura.

Dashwood, Roderick H

Mutation research. Reviews in mutation research

2020 Volume 786, Page(s) 108337

Abstract: Takashi Sugimura, M.D., Honorary President of the National Cancer Center in Tokyo, and former President of The Japan Academy, is regarded by many as a pre-eminent contributor to the field of environmental genotoxicology. His pioneering spirit led to many ...

Abstract	Takashi Sugimura, M.D., Honorary President of the National Cancer Center in Tokyo, and former President of The Japan Academy, is regarded by many as a pre-eminent contributor to the field of environmental genotoxicology. His pioneering spirit led to many key discoveries over a long and distinguished scientific career, including the first preclinical models for gastric cancer, identification of novel mutagens from cooked food, and the development of fundamental concepts in environmental chemical carcinogenesis. With his passing on September 6, 2020, many will reflect on the loss of an astute and engaging "Scientific Giant," who with warmth and good humor maintained lasting friendships both at home and abroad, beyond his many important scientific contributions.
MeSH term(s)	Animals ; Butterflies ; Carcinogenesis/chemically induced ; Carcinogens, Environmental/history ; Carcinogens, Environmental/isolation & purification ; History, 20th Century ; History, 21st Century ; Humans ; Methylnitronitrosoguanidine/history ; Methylnitronitrosoguanidine/isolation & purification ; Mutagenicity Tests/history ; Mutagens/history ; Mutagens/isolation & purification ; Stomach Neoplasms/history
Chemical Substances	Carcinogens, Environmental ; Mutagens ; Methylnitronitrosoguanidine (12H3O2UGSF)
Language	English
Publishing date	2020-10-10
Publishing country	Netherlands
Document type	Biography ; Historical Article ; Journal Article ; Portrait
ZDB-ID	2727833-5
ISSN	1388-2139 ; 1383-5742
ISSN (online)	1388-2139
ISSN	1383-5742
DOI	10.1016/j.mrrev.2020.108337
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 1316 -Rev-: Show issues

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Article ; Online: Cancer interception by interceptor molecules

Roderick H. Dashwood

Genes and Environment, Vol 43, Iss 1, Pp 1-

mechanistic, preclinical and human translational studies with chlorophylls

2021 Volume 9

Abstract: Abstract Before ‘cancer interception’ was first advocated, ‘interceptor molecules’ had been conceived as a sub-category of preventive agents that interfered with the earliest initiation steps in carcinogenesis. Three decades ago, a seminal review ... ...

Abstract	Abstract Before ‘cancer interception’ was first advocated, ‘interceptor molecules’ had been conceived as a sub-category of preventive agents that interfered with the earliest initiation steps in carcinogenesis. Three decades ago, a seminal review cataloged over fifty synthetic agents and natural products that were known or putative interceptor molecules. Chlorophylls and their derivatives garnered much interest based on the potent antimutagenic activity in the Salmonella assay, and the subsequent mechanistic work that provided proof-of-concept for direct molecular complexes with planar aromatic carcinogens. As the ‘interceptor molecule’ hypothesis evolved, mechanistic experiments and preclinical studies supported the view that chlorophylls can interact with environmental heterocyclic amines, aflatoxins, and polycyclic aromatic hydrocarbons to limit their uptake and bioavailability in vivo. Support also came from human translational studies involving ultralow dose detection in healthy volunteers, as well as intervention in at-risk subjects. Antimutagenic and antigenotoxic effects of natural and synthetic chlorophylls against small alkylating agents also highlighted the fact that non-interceptor mechanisms existed. This gave impetus to investigations broadly related to free radical scavenging, anti-inflammatory effects, immune modulation and photodynamic therapy. Therapeutic aspects of chlorophylls also were investigated, with evidence for cell cycle arrest and apoptosis in human cancer cells. As the science has evolved, new mechanistic leads continue to support the use and development of chlorophylls and their porphyrin derivatives for cancer interception, beyond the initial interest as interceptor molecules.
Keywords	Antimutagen ; Apoptosis ; Cancer interception ; Desmutagens ; Molecular complexes ; Ribonucleotide reductase ; Ecology ; QH540-549.5 ; Genetics ; QH426-470
Subject code	610
Language	English
Publishing date	2021-03-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals.

Bhattacharjee, Shamee / Dashwood, Roderick H

Antioxidants (Basel, Switzerland)

2020 Volume 9, Issue 9

Abstract: Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the ... ...

Abstract	Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the reversible nature of epigenetic alterations provides an attractive avenue for cancer interception. Thus, targeting epigenetic mechanisms in the corresponding signaling networks represents an enticing strategy for therapeutic intervention with dietary phytochemicals acting at transcriptional, post-transcriptional, and post-translational levels. This regulation involves the interplay of histone modifications and DNA methylation states in the human
Language	English
Publishing date	2020-09-14
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox9090865
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Article ; Online: Emerging crosstalk between long non-coding RNAs and Nrf2 signaling.

Bhattacharjee, Shamee / Li, Jia / Dashwood, Roderick H

Cancer letters

2020 Volume 490, Page(s) 154–164

Abstract: Diverse stimuli trigger Nrf2 signaling, which in turn transcriptionally regulates an array of downstream targets, providing for multiple layers of control. While Nrf2 activity largely is governed by posttranslational modification of critical thiol ... ...

Abstract	Diverse stimuli trigger Nrf2 signaling, which in turn transcriptionally regulates an array of downstream targets, providing for multiple layers of control. While Nrf2 activity largely is governed by posttranslational modification of critical thiol residues in the protein partner and redox sensor Keap1, fine-tuning is provided by additional mechanisms - including epigenetic regulation. Herein, we review the emerging significance of long non-coding RNAs (lncRNA) as downstream targets and upstream regulators of the Nrf2 signaling pathway. Among the ~16000 lncRNAs in GENCODE, some have been validated as transcriptionally regulated by Nrf2 (e.g., LUCAT1, NMRAL2P, ODRUL, ROR and TUG1), and others have been identified as upstream regulators of Nrf2 expression (e.g., HOTAIR, MALAT1, MEG1, NRAL and UCA1). Bioinformatic analyses of annotated human lncRNAs identified putative Nrf2 binding sites in the promoter regions of 13,285 lncRNAs. Further investigation is warranted to validate the many novel lncRNAs as bona fide Nrf2-regulated targets, and their roles in Nrf2 signaling. Nrf2 is considered a promising therapeutic candidate for cancer and other chronic diseases; thus, targeting the associated lncRNAs might provide for a more refined fine-tuning of the system, depending on cellular and pathophysiological context.
MeSH term(s)	Gene Expression Regulation/physiology ; Humans ; NF-E2-Related Factor 2/metabolism ; RNA, Long Noncoding/metabolism ; Signal Transduction/physiology
Chemical Substances	NF-E2-Related Factor 2 ; NFE2L2 protein, human ; RNA, Long Noncoding
Language	English
Publishing date	2020-07-24
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	195674-7
ISSN	1872-7980 ; 0304-3835
ISSN (online)	1872-7980
ISSN	0304-3835
DOI	10.1016/j.canlet.2020.07.011
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Zs.A 1177: Show issues

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Je nach Verfügbarkeit (siehe Angabe bei Bestand)
bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: CCAR1 and CCAR2 as gene chameleons with antagonistic duality: Preclinical, human translational, and mechanistic basis.

Johnson, Gavin S / Rajendran, Praveen / Dashwood, Roderick H

Cancer science

2020 Volume 111, Issue 10, Page(s) 3416–3425

Abstract: Cell Cycle and Apoptosis Regulator 1 (CCAR1) and Cell Cycle and Apoptosis Regulator 2 (CCAR2) have emerged as key players in physiology and pathophysiology, with critical roles in the DNA damage response, nuclear receptor function, and Wnt signaling, ... ...

Abstract	Cell Cycle and Apoptosis Regulator 1 (CCAR1) and Cell Cycle and Apoptosis Regulator 2 (CCAR2) have emerged as key players in physiology and pathophysiology, with critical roles in the DNA damage response, nuclear receptor function, and Wnt signaling, among other activities. Contradictory reports exist on the functional duality of CCAR1 and CCAR2 as either tumor promoters or suppressors, suggesting that CCAR1 and CCAR2 have the hallmarks of gene chameleons. We review herein the mechanistic, preclinical, and human translational findings for CCAR1 and CCAR2, based on available RNA and protein expression data from human studies, The Cancer Genome Atlas (TCGA) data mining, gene knockout mouse models, and cell-based assays. Multiple factors contribute to the divergent activities of CCAR1 and CCAR2, including tissue type, mutation/genetic background, protein-protein interactions, dynamic regulation via posttranslational modifications, and alternative RNA splicing. An array of protein partners interact with CCAR1 and CCAR2 in the context of tumor promotion and suppression, including β-catenin, androgen receptor, p21
MeSH term(s)	Adaptor Proteins, Signal Transducing/genetics ; Animals ; Apoptosis Regulatory Proteins/genetics ; Cell Cycle Proteins/genetics ; Disease Models, Animal ; Genes, Tumor Suppressor ; Humans ; Mice ; Mice, Knockout ; Neoplasms/genetics ; Promoter Regions, Genetic
Chemical Substances	Adaptor Proteins, Signal Transducing ; Apoptosis Regulatory Proteins ; CCAR1 protein, human ; CCAR1 protein, mouse ; CCAR2 protein, human ; Cell Cycle Proteins
Language	English
Publishing date	2020-08-09
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2115647-5
ISSN	1349-7006 ; 1349-7006
ISSN (online)	1349-7006
ISSN	1349-7006
DOI	10.1111/cas.14579
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Epigenetic Regulation of NRF2/KEAP1 by Phytochemicals

Bhattacharjee, Shamee / Dashwood, Roderick H

Antioxidants. 2020 Sept. 14, v. 9, no. 9

2020

Abstract: Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2–related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the ... ...

Abstract	Epigenetics has provided a new dimension to our understanding of nuclear factor erythroid 2–related factor 2/Kelch-like ECH-associated protein 1 (human NRF2/KEAP1 and murine Nrf2/Keap1) signaling. Unlike the genetic changes affecting DNA sequence, the reversible nature of epigenetic alterations provides an attractive avenue for cancer interception. Thus, targeting epigenetic mechanisms in the corresponding signaling networks represents an enticing strategy for therapeutic intervention with dietary phytochemicals acting at transcriptional, post-transcriptional, and post-translational levels. This regulation involves the interplay of histone modifications and DNA methylation states in the human NFE2L2/KEAP1 and murine Nfe2l2/Keap1 genes, acetylation of lysine residues in NRF2 and Nrf2, interaction with bromodomain and extraterminal domain (BET) acetyl “reader” proteins, and non-coding RNAs such as microRNA (miRNA) and long non-coding RNA (lncRNA). Phytochemicals documented to modulate NRF2 signaling act by reversing hypermethylated states in the CpG islands of NFE2L2 or Nfe2l2, via the inhibition of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs), through the induction of ten-eleven translocation (TET) enzymes, or by inducing miRNA to target the 3′-UTR of the corresponding mRNA transcripts. To date, fewer than twenty phytochemicals have been reported as NRF2 epigenetic modifiers, including curcumin, sulforaphane, resveratrol, reserpine, and ursolic acid. This opens avenues for exploring additional dietary phytochemicals that regulate the human epigenome, and the potential for novel strategies to target NRF2 signaling with a view to beneficial interception of cancer and other chronic diseases.
Keywords	DNA ; DNA methylation ; acetylation ; antioxidants ; chronic diseases ; curcumin ; epigenetics ; genes ; genomic islands ; histone code ; histone deacetylase ; humans ; lysine ; methyltransferases ; mice ; microRNA ; non-coding RNA ; nucleotide sequences ; phytochemicals ; proteins ; reserpine ; resveratrol ; sulforaphane ; therapeutics ; transcription (genetics) ; ursolic acid
Language	English
Dates of publication	2020-0914
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
Note	NAL-light
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox9090865
Database	NAL-Catalogue (AGRICOLA)

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Article: Targeting Epigenetic 'Readers' with Natural Compounds for Cancer Interception.

Damiani, Elisabetta / Duran, Munevver N / Mohan, Nivedhitha / Rajendran, Praveen / Dashwood, Roderick H

Journal of cancer prevention

2021 Volume 25, Issue 4, Page(s) 189–203

Abstract: Natural compounds from diverse sources, including botanicals and commonly consumed foods and beverages, exert beneficial health effects via mechanisms that impact the epigenome and gene expression during disease pathogenesis. By targeting the so-called ... ...

Abstract	Natural compounds from diverse sources, including botanicals and commonly consumed foods and beverages, exert beneficial health effects via mechanisms that impact the epigenome and gene expression during disease pathogenesis. By targeting the so-called epigenetic 'readers', 'writers', and 'erasers', dietary phytochemicals can reverse abnormal epigenome signatures in cancer cells and preneoplastic stages. Thus, such agents provide avenues for cancer interception via prevention or treatment/therapeutic strategies. To date, much of the focus on dietary agents has been directed towards writers (e.g., histone acetyltransferases) and erasers (e.g., histone deacetylases), with less attention given to epigenetic readers (e.g., BRD proteins). The drug JQ1 was developed as a prototype epigenetic reader inhibitor, selectively targeting members of the bromodomain and extraterminal domain (BET) family, such as BRD4. Clinical trials with JQ1 as a single agent, or in combination with standard of care therapy, revealed antitumor efficacy but not without toxicity or resistance. In pursuit of second-generation epigenetic reader inhibitors, attention has shifted to natural sources, including dietary agents that might be repurposed as 'JQ1-like' bioactives. This review summarizes the current status of nascent research activity focused on natural compounds as inhibitors of BET and other epigenetic 'reader' proteins, with a perspective on future directions and opportunities.
Language	English
Publishing date	2021-01-06
Publishing country	Korea (South)
Document type	Journal Article ; Review
ZDB-ID	3019805-7
ISSN	2288-3657 ; 2288-3649
ISSN (online)	2288-3657
ISSN	2288-3649
DOI	10.15430/JCP.2020.25.4.189
Database	MEDical Literature Analysis and Retrieval System OnLINE

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