HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates

Rajendran, Praveen; Kidane, Ariam I.; Yu, Tianwei; Dashwood, Wan‐Mohaiza; Bisson, William H.; Löhr, Christiane V.; Ho, Emily; Williams, David E.; Dashwood, Roderick H.

doi:10.4161/epi.24710

Cited by 105 publications

(140 citation statements)

References 47 publications

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“…SFN has previously been shown to inhibit histone deacetylase activity (18,45,56). In human volunteers, a single ingestion of a small amount of broccoli sprouts (ϳ70 g), which contain particularly high amounts of SFN, inhibits histone deacetylase activity in circulating peripheral blood mononuclear cells and consequently induces histone H3 and H4 acetylation a few hours after intake (56).…”

Section: Discussionmentioning

confidence: 99%

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Thaler

Maurizi

Roschger

et al. 2016

Journal of Biological Chemistry

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Bone degenerative pathologies like osteoporosis may be initiated by age-related shifts in anabolic and catabolic responses that control bone homeostasis. Here we show that sulforaphane (SFN), a naturally occurring isothiocyanate, promotes osteoblast differentiation by epigenetic mechanisms. SFN enhances active DNA demethylation via Tet1 and Tet2 and promotes preosteoblast differentiation by enhancing extracellular matrix mineralization and the expression of osteoblastic markers (Runx2, Col1a1, Bglap2, Sp7, Atf4, and Alpl). SFN decreases the expression of the osteoclast activator receptor activator of nuclear factor-B ligand (RANKL) in osteocytes and mouse calvarial explants and preferentially induces apoptosis in preosteoclastic cells via up-regulation of the Tet1/Fas/Caspase 8 and Caspase 3/7 pathway. These mechanistic effects correlate with higher bone volume (ϳ20%) in both normal and ovariectomized mice treated with SFN for 5 weeks compared with untreated mice as determined by microcomputed tomography. This effect is due to a higher trabecular number in these mice. Importantly, no shifts in mineral density distribution are observed upon SFN treatment as measured by quantitative backscattered electron imaging. Our data indicate that the food-derived compound SFN epigenetically stimulates osteoblast activity and diminishes osteoclast bone resorption, shifting the balance of bone homeostasis and favoring bone acquisition and/or mitigation of bone resorption in vivo. Thus, SFN is a member of a new class of epigenetic compounds that could be considered for novel strategies to counteract osteoporosis.

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Section: Discussionmentioning

confidence: 99%

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Thaler

Maurizi

Roschger

et al. 2016

Journal of Biological Chemistry

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“…In yeast, autophagy targets the DNA damage repair protein Sae2 (orthologous to human RBBP8) for autophagic degradation upon its acetylation, 28 and autophagy has also been implicated in regulating levels of RBBP8 in human colon cancer cells. 29 These data suggest that autophagy may control DNA damage repair in mammalian cells through the regulation of RBBP8, a key protein mediating the choice between nonhomologous and homologous repair pathways. 49 Autophagy has also been shown to influence cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

“…Initial studies showed that autophagy promotes genome stability by maintaining cellular metabolic homeostasis, 27 and more recent work in yeast and mammalian cells suggests that autophagy directly influences DNA damage repair by modulating levels of the key repair protein RBBP8/ CtIP. 28,29 Moreover, autophagy guards against aneuploidy by regulating cell cycle progression and cytokinesis. 30,31 In light of these emerging roles for autophagy in senescence and genome instability, 2 critical sequelae of telomere dysfunction, we sought to delineate the potential functions of autophagy in the cellular response to acute telomere dysfunction.…”

Section: Introductionmentioning

confidence: 99%

Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction

Mar¹,

Debnath²,

Stohr³

2015

Autophagy

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Abbreviations: ACD/Tpp1, adrenocortical dysplasia homolog (mouse); ATG5, autophagy-related 5, ATG7, autophagy-related 7; B2M, b-2-microglobulin; HBSS, Hank's buffered salt solution; HMECs, human mammary epithelial cells; MEFs, mouse embryonic fibroblasts; MT-HsTER, mutant template-Homo sapiens template-containing RNA; MT-MmTER, mutant template-Mus musculus template-containing RNA; OIS, oncogene-induced senescence; RBBP8/CtIP, retinoblastoma binding protein 8; SA-b-Gal, senescence-associated b-galactosidase; SASP, senescence associated secretory phenotype; TDIS, telomere dysfunction-induced senescence; TERT, telomerase reverse transcriptase; TIFs, telomere dysfunction-induced foci.Telomere dysfunction plays a complex role in tumorigenesis. While dysfunctional telomeres can block the proliferation of incipient cancer clones by inducing replicative senescence, fusion of dysfunctional telomeres can drive genome instability and oncogenic genomic rearrangements. Therefore, it is important to define the regulatory pathways that guide these opposing effects. Recent work has shown that the autophagy pathway regulates both senescence and genome instability in various contexts. Here, we apply models of acute telomere dysfunction to determine whether autophagy modulates the resulting genome instability and senescence responses. While telomere dysfunction rapidly induces autophagic flux in human fibroblast cell lines, inhibition of the autophagy pathway does not have a significant impact upon the transition to senescence, in contrast to what has previously been reported for oncogene-induced senescence. Our results suggest that this difference may be explained by disparities in the development of the senescence-associated secretory phenotype. We also show that chromosome fusions induced by telomere dysfunction are comparable in autophagy-proficient and autophagy-deficient cells. Altogether, our results highlight the complexity of the senescence-autophagy interface and indicate that autophagy induction is unlikely to play a significant role in telomere dysfunction-driven senescence and chromosome fusions.

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“…Studies involved in the evaluation of sulforaphane as an HDAC inhibitor, and those aimed at providing insights into the mechanisms associated with sulforaphane-regulated inhibition of HDAC activity, have focused on the roles of HDAC3 and HDAC6 as important targets (43, 89,223,224). After the incubation of HCT116 human colon cancer cells with 15 lM sulforaphane, a significant reduction in HDAC1, HDAC2, HDAC3, and HDAC8 was observed compared with vehicle-treated cells at 36 h post administration (223).…”

mentioning

confidence: 99%

Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition

Tortorella

Royce²,

Licciardi

et al. 2015

Antioxidants & Redox Signaling

182

110

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Significance: Sulforaphane, produced by the hydrolytic conversion of glucoraphanin after ingestion of cruciferous vegetables, particularly broccoli and broccoli sprouts, has been extensively studied due to its apparent health-promoting properties in disease and limited toxicity in normal tissue. Recent Studies: Recent identification of a sub-population of tumor cells with stem cell-like self-renewal capacity that may be responsible for relapse, metastasis, and resistance, as a potential target of the dietary compound, may be an important aspect of sulforaphane chemoprevention. Evidence also suggests that sulforaphane may target the epigenetic alterations observed in specific cancers, reversing aberrant changes in gene transcription through mechanisms of histone deacetylase inhibition, global demethylation, and microRNA modulation. Critical Issues: In this review, we discuss the biochemical and biological properties of sulforaphane with a particular emphasis on the anticancer properties of the dietary compound. Sulforaphane possesses the capacity to intervene in multistage carcinogenesis through the modulation and/or regulation of important cellular mechanisms. The inhibition of phase I enzymes that are responsible for the activation of pro-carcinogens, and the induction of phase II enzymes that are critical in mutagen elimination are well-characterized chemopreventive properties. Furthermore, sulforaphane mediates a number of anticancer pathways, including the activation of apoptosis, induction of cell cycle arrest, and inhibition of NFjB. Future Directions: Further characterization of the chemopreventive properties of sulforaphane and its capacity to be selectively toxic to malignant cells are warranted to potentially establish the clinical utility of the dietary compound as an anticancer compound alone, and in combination with clinically relevant therapeutic and management strategies.

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HDAC turnover, CtIP acetylation and dysregulated DNA damage signaling in colon cancer cells treated with sulforaphane and related dietary isothiocyanates

Cited by 105 publications

References 47 publications

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Anabolic and Antiresorptive Modulation of Bone Homeostasis by the Epigenetic Modulator Sulforaphane, a Naturally Occurring Isothiocyanate

Autophagy-independent senescence and genome instability driven by targeted telomere dysfunction

Dietary Sulforaphane in Cancer Chemoprevention: The Role of Epigenetic Regulation and HDAC Inhibition

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