Sulforaphane from broccoli, an epigenetic modulator in cancer cells

Abstract

The consumption of cruciferous vegetables offers several health benefits due to some of their compounds. Sulforaphane (SFN), a compound found in cabbage and broccoli, has received special attention in recent years due to its anticancer activities. The main objective of this systematic review is to examine the epigenetic and genetic effects of SFN on cancers (in vitro and in vivo) which contribute to its anticancer activities. We only analyzed studies that combined its epigenetic effects and anticancer activities due to the multitude of studies on SFN over the past few years. We found that SFN is able to regulate epigenetic mechanisms and promote the prevention and treatment of several cancers. Definitely, it prevents tumor growth and acts as a histone deacetylase (HDAC) inhibitor, a DNA methyltransferase (DNMT) inhibitor, and a microRNA regulator in several cancers. These epigenetic regulations lead indirectly to a hyperregulation or deregulation of the expression of genes involved in carcinogenesis. SFN hasn’t any major epigenetic effect on normal cells. This review revealed that the anticancer activities attributable to SFN are largely related to its ability to modulate cancer cell epigenome. These capabilities to modulate the epigenome make SFN a promising anticancer agent with significant therapeutic potential.

Background

Cancer today is seemingly considered as a significant factor of morbidity. Any person diagnosed late with cancer has a poor prognosis. This disease has increased considerably the rate of mortality all around the world, in spite of the development of the country and its progress in medical domain. In 2020, a survey conducted by IARC (International Agency for Research) on cancer shows that the global burden of cancer was estimated at around 19.3 million of new cases and nearly 10 million of these cases resulted in death. And according to the prognostic of IARC, it is estimated by 2040, the cases would rise up to 28.4 million, an increase of 47% compared to the 2020 estimates, if no action is taken. In Burkina Faso, precisely in 2020, 12,045 new cases related to cancer were registered and among them, 8,695 deaths were cancer-related according to the IARC. These incidents are becoming more and more common in Burkina Faso, and happen at a relatively young age [1].

Cancer is a disease in which cells develop uncontrollably in the body [2]. Several studies have highlighted the cancer development according to numerous factors. Factors such as age, sex, heredity, reproductive factors, diet, presence of other cancers, anthropometric characteristics, psychological and environmental factors are all considered as possible risk factors [3]. Carcinogenesis is a long-term process that may take 10–30 years to evolve from initial stage to advanced stage, eventually leading to a metastatic cancer [4]. There is a multi-step by which cancer cells escape apoptosis, acquire unlimited potential division in order to have the ability to invade normal tissues [5]. This process is divided into three phases such as the initiation phase, the promotion phase and the progression phase [4].

Current evidence increasingly demonstrates that cancer is not only linked to genetic alterations but also to modifications in DNA sequences [6]. Genetic change and epigenetic mechanisms impact genes controlling genetic stability, cell death, and proliferation [7, 8]. Epigenetic mechanisms concern all mechanisms that control gene expression without changing the DNA sequences [8]. Gene expression profiles in normal cells are maintained by epigenetic mechanisms [8]. These mechanisms also help regulate the abnormal expressions of the genes within the cells [9]. They can be classified into three categories such as the histone modification, the non-coding RNA expression and the DNA methylation.

DNA methylation is a pertinent epigenetic modification. The DNA methyltransferases (DNMTs) ensure the establishment as well as the maintenance of these DNA methylation models. Three of the DNMTs were identified in higher eukaryotes. DNMT1, which plays an important role in maintaining the methylation, and DNMT3a and DNMT3b, which help catalyze the de novo methylation [9, 10]. Data have demonstrated the significant role of DNMTs in monitoring the level of DNA methylation. Clinically, all DNMT subtypes are strongly expressed in cancers, and DNMT overexpression can result in hypermethylation of promoters of tumor suppressor genes and tumorigenesis [8, 9]. Indeed, the first cancerous epigenome is characterized by a hypermethylation of CpG islands of the tumor suppressor genes’ promoters, which leads to their inactivation. Another epigenetic hallmark of cancer global DNA hypomethylation, particularly in oncogenes and repetitive regions, which causes irregular expression of microRNAs, activation of oncogenes and repression or silencing of tumor suppressor genes [8, 10–12]. This hypermethylation of promoters can cause a disruption of the mechanisms that regulate the progression of the cell cycle, the DNA repair and the apoptosis. In short, DNMT overexpression can lead to aberrant DNA methylation, which is broadly observed in several cancers. It is imperative to note that this aberrant DNA methylation is reversible, and as a result, DNMTs have become an important target for cancer treatment and/or prevention. DNA methyltransferase inhibitors (DNMTIs) are used in the field of chemotherapy [10]. The treatment using 5-azadeoxycytidine (a DNMT inhibitor) has been act effective against cell growth. Nevertheless, the use of this product as a cancer chemoprotective/therapeutic remedy is limited due to its toxicity and unspecific gene targeting [13]. In addition to DNA methylation, histone modification is another important target in the fight against cancer.

Histone modifications include phosphorylation, acetylation, ubiquitination, and methylation [14] but only the methylation and the acetylation are the most studied. Both of them have the ability to regulate access to transcription factors [15]. Histone methyltransferases catalyze histone methylation and this leads to an activation or silencing of gene [15]. This review focused on the histone acetylation/deacetylation. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) control acetylation. HAT neutralizes the histone charge by transferring an acetyl group to lysine residues in the histone tails, resulting from a loosening of chromatin structure. Unlike HATs, HDACs promote chromatin compaction by deacetylating histone tails. HDAC can also deacetylate proteins other than histones, such as transcription factors and other proteins [16, 17]. The classic HDAC family is made up of 11 members; which are divided into four classes: class I, class IIa, class IIb and class IV. Class I is expressed in all tissues and contains HDACs 1, 2, 3, and 8. They are present in the nucleus and largely responsible for histone deacetylation. Class IIa includes HDACs 4, 5, 7, and 9. They are found primarily in the heart, brain, muscles, thymocytes and endothelial cells. Class IIb includes HDAC6 and 10. HDAC6 is mainly localized in the cytoplasm and plays a role in regulating cytotoxicity [17]. Little information is known about HDAC10. Class IV includes a single-element HDAC11 [16]. As altered HDAC expression is frequently observed in various cancers, histone deacetylase inhibitors (HDACIs) have been extensively investigated [10]. Trichostatin A (an HDAC inhibitor) has been shown to suppress cancer cell progression but it has side effects and non-specific in the modulation of gene [13]. In addition to DNA methylation and histone modification, epigenetic mechanisms also involve the expression of non-coding RNAs.

There are several types of non-coding RNA such as transfer RNA, ribosomal RNA, small nuclear and nucleolar RNAs, small Cajal RNA, microRNA, and others. MicroRNA (miRNA or miR) is single-stranded small RNA of 20–22 nucleotides, which regulate target gene expressions, often by inducing translational repression or degradation of mRNA. They regulate over 30% of human protein-coding genes and have been involved in controlling cell activity, such as proliferation, differentiation and apoptosis. They also play an important role in carcinogenesis [18, 19]. One the one hand, the full complementarity between miRNAs and target mRNAs results in degradation of the mRNA sequences. Partial complementarity, on the other hand, blocks protein translation (report in [20]). In both cases, the corresponding genes are not expressed. Tumor suppressor miRNAs are associated with decreased tumor proliferation and viability, and contribute into apoptotic, whereas their down-regulation induces cancer cells proliferation [18]. The disruption of miRNAs leads to abnormalities in gene expression and in cell signaling pathways involved in cancers [7, 19]. These perturbations are reversible. The search for substances or compounds capable of restoring miRNA levels is a goal in the field of cancer therapy.

In short, epigenetic alterations in cancer are receiving cumulative attention. Evidences have shown that epigenetic dysregulations, such as an increased activity of HDAC and DNMTs, and changes in non-coding RNA expression can cause changes in the transcription and expression of genes involved in cellular mechanisms [12, 21] (Fig. 1). These epigenetic abnormalities can be easily reversed [10, 22, 23]. In fact, basing on a thorough understanding of the epigenetic dysregulation involved in tumorigenesis, DNMTIs and HDACIs have been used in cancer therapy [24]. Among the natural components, cruciferous plants also regulate epigenetic mechanisms due to their high content of glucosinolates.

Fig. 1.

Aberrant epigenetic mechanisms in carcinogenesis. Green arrows represent “inductions” and red lines represent “inhibitions”. Aberrant epigenetic mechanisms lead to overexpression of HDACs and DNMTs enzymes, expression of oncomiRNAs and inhibition of tumor suppressor miRNAs. All of this contributes to the repression of tumor suppressor genes and therefore to the development of cancer. Adapted by Dabré et al. (2024)

Cruciferous plants are generally derived from the genus Brassica, including cabbage, broccoli, Brussels sprouts, kohlrabi, mustard, etc [25]. Broccoli is also a significant source of antioxidants, micronutrients and phytochemicals [26–28]. Various phytochemical tests carried out on broccoli have also revealed the presence of terpenoids, tannins, phenolic compounds and phytosterols [29]. The consumption of cruciferous plants such as broccoli and cabbage, is known to be a protective aspect against cancer. Studies have shown that broccoli contains high concentrations of glucosinolates, which inhibit the proliferation of cancer cells. This content of broccoli glucosinolates can be also influenced by cooking and plant’s stage. It is higher in seeds and young shoots than in other parts of the plant [30, 31].The main glucosinolate found in broccoli is glucoraphanin, which is transformed into sulforaphane (SFN) by myrosinase [32]. This enzyme is physically separated from the glucosinolates in plant cells, but it is released when the cells are damaged by chewing or grinding, resulting in the mixing of glucosinolates and myrosinase. This conversion can also be mediated by the microflora of the gastrointestinal tract of mammals [33]. Studies report that SFN possesses strong antitumor activities. It prevents carcinogenesis through distinct epigenetic mechanisms, such as histone acetylation, DNA demethylation, and altered expression of non-coding RNA [34].

The present article review aims to highlight the different conducted research based on the epigenetic effects of SFN in cancer. To the end, we have identified and analyzed several epigenetic searches on PubMed and Google Scholar. We found that SFN acts as a powerful epigenetic modulator notably as a histone deacetylase inhibitor, DNA methyltransferase inhibitor and microRNA regulator.

Methodology

Data sources and searches

This systematic review was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [35] and the selection process is presented in Fig. 2. Data searches were carried out from July 11 to July 20,2024, using two well-known scientific databases: PubMed and Google Scholar. Articles were identified based on a combination of keywords and MeSH terms. The search equation used was: (“Sulforaphane”) AND (“epigenetic” OR “genetic”) AND (“Cancer” OR “Carcinoma” OR “Tumor”) adapting the search method to each database.

Fig. 2.

Selection process in the current study in accordance with PRISMA

Selection criteria

Only articles published between January 1, 2009 and July 20, 2024, were included. Articles were selected on the basis of the relevant titles and abstracts in each database. Full-text articles were reviewed, duplicate articles and review articles were excluded. Inclusion criteria for this study were: (1) full-text articles focusing on sulforaphane and its epigenetic effects on cancer; (2) papers published within the last 15 years (2009–2024); (3) written in English.

Exclusion criteria were: (1) articles for which a full text is not available (2) article that does not use sulforaphane as main a theme (3) article that does not deal with original data (such as reviews, commentaries, letters, and case reports). (4) article that does not describe DNA methylations, histone acetylation or miRNA expressions.

Results

Study characteristics and quality

We initially identified a total of 679 articles (200 from PubMed and 479 from GoogleScholar). Among the 679 references, 380 were excluded because they were duplicates. After an initial selection based on titles and abstracts, 186 articles were excluded (3 non-English papers; 30 non-available full-text articles; 153 reviews and meta-analyses). 113 articles were retained and subjected to in-depth evaluation. Among these 113 articles, 78 studies were excluded for the following reasons: (i) articles that do not deal with Sulforaphane (19 studies); (ii) articles that do not deal with epigenetic (18 studies); (iii) articles that do not deal with epigenetic effects of sulforaphane and cancer (41 studies). Finally, 35 articles were selected for this systematic review. 29 articles deal with histone modifications and DNA methylation and 6 are related to miRNA regulation. The exclusion process is illustrated in Fig. 2.

Sulforaphane induces apoptosis and selectively inhibits cell proliferation in cancer cells

Several studies precisely on in vitro and in vivo have evaluated the effect of SFN alone or in combination with other molecules on apoptosis and cell proliferation. The induction of apoptosis was observed in prostate cancer cells (BPH1, LnCap, PC3) [17], human gastric cancer cell lines (AGS, MKN45) [34], breast cancer cells [8], lung cancer cells [36], acute myeloid leukemia [37] after treatment with SFN. In short, SFN alone and/or in combination with other molecules significantly inhibits cell proliferation, depending on the time and dose, in various cancers such as skin cancer [38, 39], colorectal cancer [40, 41], melanoma [15, 42], breast cancer [43–45].

Bauman et al. [46] studied the potential chemopreventive activity of sulforaphane using an in vivo mouse model of carcinogen oral cancer. Their study demonstrated that SFN reduced the incidence and size of tongue tumors in mice treated with 4NQO. SFN combined with other compounds has the ability to prevent the growth of mammary tumor xenografts in mice [44, 47]. In addition, Brane et al. [48] showed that administration of broccoli sprouts during the peri-puberty period resulted in a decreased breast tumor formation in SV40 and HER2/neu mice (reduced incidence and weight of tumor, and increased tumor latency). Similarly, Li et al. [43] found that paternal administration of broccoli sprouts and/or green tea polyphenols significantly inhibited mammary tumor progression in both C3 and HER2/neu mice (female offspring). Interestingly, no effect was observed on normal cells in these studies [8, 17, 34].

As a partial conclusion, SFN has the ability to suppress tumors by inducing apoptosis in cancer cells. In vivo studies have also confirmed that SFN diminishes tumor size of the tumors in organisms. Overall, SFN appears to selectively induce apoptosis in cancer cells without affecting normal cells.

Sulforaphane acts on cell cycle arrest and senescence

SFN induces cell cycle arrest. To illustrate it, Lewinska et al. [8] showed that SFN (5 and 10 µM) can induce cell accumulation in the G0/G1 or G2/M phases of the cell cycle and senescent activity in breast cancer lines. Similarly, Clarke et al. [17] observed a strong induction of G2/M cell cycle arrest after SFN treatment in prostate cancer cells, but SFN had no effect on the cell cycle of normal prostate epithelial cells. SFN also induces arrest of SCC-13 cells in G2/M phase [38]. SFN combined with genistein inhibits cell cycle progression in G2 phase for MDA-MB-231 and in G1 phases for MCF-7 in breast cancer [49]. Martin et al. [41] found that SFN induced cell cycle arrest in G2/M phase at an optimal dose of 10 µM.

Overall, senescence and cell cycle arrest are mechanisms through which SFN also suppresses cancer cells, while sparing normal cells.

Sulforaphane inhibits cancer formation and progression through epigenetic mechanisms

Sulforaphane regulates histone acetylation

SFN, a natural cruciferous compound known for its potent anticancer activities, has been recognized as a HDAC inhibitor in cancer models in vivo and in vitro [8, 9, 23, 50].

Several studies have demonstrated that SFN (alone or combined with other molecules) can modulate histone acetylation by decreasing HDAC gene expression and enzyme activity [44]. The present review has revealed that this decrease affects all HDAC classes in numerous cancers such as breast cancer [8, 24, 43–45, 51–54], prostate cancer [13, 17, 55], bladder cancer [14], cervix cancer [56], skin cancer including melanoma [15, 22] and colon cancer [41]. The Table 1 summarizes the different HDAC classes downregulated by SFN (alone or in combination) in various cancer. This decrease in HDAC activity can result from direct inhibition of HDAC mRNA transcription or from alteration of HDAC protein levels (see Fig. 3a). Therefore, SFN acts as a potent HDAC inhibitor in cancer cells. In addition to the decreasing HDAC mRNA levels and/or their proteins, several studies have observed an increase in histone acetylation in cancer cells following SFN treatment [17, 44]. Exceptionally, Lewinska et al. [8] found that SFN increased HDAC5 mRNA levels in three breast cancer cells (MCF-7 cells, MDA-MB-231 cells and SK-BR-3 cells).

Table 1.

Epigenetic mechanisms regulated by SFN (alone or combinatory) in cancers

Epigenetics events	Association with cancers	Regulation by SFN	References
Histones deacetylases (HDACs)
HDAC 1	Breast, prostate, bladder, skin, cervix, colorectal cancers	Downregulated	[13–15, 22, 24, 41, 43–45, 51–54, 56]
HDAC 2	Breast, prostate, bladder, skin cancers	Downregulated	[8, 14, 15, 17, 22, 51, 52]
HDAC 3	Breast, prostate, skin cancers	Downregulated	[8, 17, 22, 51, 52, 55]
HDAC 4	Breast, prostate, bladder, skin cancers	Downregulated	[8, 13–15, 17, 22, 43]
HDAC 5	Prostate	Downregulated	[13]
HDAC 6	Breast, prostate, bladder, skin cancers	Downregulated	[8, 14, 15, 17, 43]
HDAC 7	Breast, prostate cancers	Downregulated	[8, 13]
HDAC 8	Breast cancer	Downregulated	[8]
HDAC 9	Breast cancer	Downregulated	[8]
HDAC 10	Breast cancer	Downregulated	[8]
HDAC 11	Breast cancer	Downregulated	[43]
DNA methyltransferases (DNMTs)
DNMT 1	Breast, prostate, skin, colorectal cancers	Downregulated	[8, 13, 22, 24, 43–45, 54, 57, 58]
DNMT 3a	Breast, prostate, skin cancers	Downregulated	[8, 13, 22, 24, 43, 57]
DNMT 3b	Breast, prostate, skin, cervix cancers	Downregulated	[8, 22, 56, 57]
MicroRNAs (miR)
miR-9	Colorectal cancer	Upregulated	[64]
miR-9-3	Lung cancer	Upregulated	[9]
miR-21	Colorectal cancer	Downregulated	[41]
miR-23b	Colorectal cancer	Upregulated	[64]
miR-23b-3p	Breast cancer	Downregulated	[8]
miR-27b	Colorectal cancer	Upregulated	[64]
miR-30a	Colorectal cancer	Upregulated	[64]
miR30a-3p	Pancreas cancer	Downregulated	[63]
miR-92b-3p	Breast cancer	Downregulated	[8]
miR-106a	Colorectal cancer	Downregulated	[64]
miR-135b	Colorectal cancer	Upregulated	[64]
miR-145	Colorectal cancer	Upregulated	[64]
miR-146a	Colorectal cancer	Upregulated	[64]
miR-155	Acute myeloid leukemia, colorectal cancer	Downregulated	[37, 64]
miR-214	Lung cancer	Upregulated	[45]
miR-326	Gastric cancer	Upregulated	[34]
miR-342-3p	Colorectal cancer	Upregulated	[64]
miR-372	Colorectal cancer	Upregulated	[64]
miR-381-3p	Breast cancer	Downregulated	[8]
miR-382-5p	Breast cancer	Downregulated	[8]
miR-486-5p	Colorectal cancer	Upregulated	[64]
miR-505	Colorectal cancer	Upregulated	[64]
miR-629	Colorectal cancer	Upregulated	[64]
miR-633	Colorectal cancer	Downregulated	[64]
miR-758	Colorectal cancer	Upregulated	[64]

Fig. 3.

SFN regulates epigenetic mechanisms. a SFN acts at transcriptional level leading to reduce HDAC mRNA and at translational resulting HDAC protein diminution. b At transcriptional level, SFN reduces DNMT mRNA and at translational, SFN decreases DNMT proteins. c SFN inhibits DNMTs and prevent DNA methylation in tumor suppressor miRNA promoter resulting in their expression

Definitively, Histone acetylation induced by SFN decreases the affinity between DNA and histones, relaxing the structure of chromatin, which makes DNA more accessible to transcription factors and promotes the expression of tumor suppressor genes.

SFN acts on DNA demethylation in cancer

SFN has been known to lessen DNA methylation in cancer cells. This hypomethylation may result from the inhibition of DNMT protein expression and/or the enzymatic activity in a concentration-dependent manner in vitro [8, 9]. In this study, we found that SFN (alone or in combination) can diminish gene and/or protein expression of all DNMT types in several cancers. DNMT 1 has been downregulated in breast [8, 24, 43–45, 54], prostate [13, 57], colorectal [58] and skin [22] cancers. DNMT 3a has been downregulated in breast [8, 24, 43], prostate [13, 57] and skin [22] cancers. DNMT 3b has been downregulated in breast [8], prostate [57], skin [22] and cervix [56] cancers. Table 1 summarizes the DNMT downregulated by SFN (alone or in combination) in cancers.

In general, DNMT catalyzes DNA methylation and its overexpression can result from the hypermethylation of tumor suppressor gene promoters, leading to tumorigenesis and poor prognosis [8, 9]. SFN decreases or impedes DNMT activity in a dose- and time-dependant manner [59], indirectly affecting on tumor suppressor gene expression. Therefore SFN is a strong inhibitor of DNMT in cancer cells (Fig. 3b).

Taken together, this report provides evidence that the downregulation of HDAC and DNMT activities are key mechanisms by which SFN exerts its effects in cancer cells. SFN is consequently regarded as a HDAC and DNMT inhibitors.

Sulforaphane modulates MicroRNA expression

Deregulation of miRNA has been implicated in cancer development. SFN performs as a miRNA regulator in many cancers.Many miRNAs were deregulated, and others were overregulated in cancer cells after SFN treatment. For instance, miR-23b-3p, miR-92b-3p, miR-381-3p, miR-382-5p, miR29b-1-5p, and miR-27b-5p were significantly lessened in SFN-treated cells [8, 60]. Treatment with sulforaphane extracted from broccoli also suppresses gastric cancer lines by modulating miR-9 and miR-326 levels [34] and increasing miR-135b-5p. This in turn, increases the rate of tumor suppressor RASAL2 in triple negative breast cancer and ovarian cancer [61]. SFN inhibits the properties of cancer stem-like cell (CSC). It improves the therapeutic efficacy of cisplatin in human non-small cell lung cancer (NSCLC) by upregulating miR-214 [36]. It can also induce greater differentiation of myeloid progenitor cells by controlling miR-155, thus attenuating the progression of acute myeloid leukemia (AML) [37]. It also appears to control the miR-19/PTEN axis resulting in protective effects against breast cancer promotion by BBP. Butyl benzyl phthalate (BBP), a widely used plasticizer, plays an important role in breast cancer promotion [62]. It also prevents miR30a-3p (correlated with malignancy). It improves gap junction intercellular communication in pancreatic cancer [63].

SFN regulation of tumor suppressor miRNAs is possible through hypomethylation of the CpG region in the miRNA promoter. Gao et al. (2018) [9] found that SFN reduces CpG methylation in the miR-9-3 promoter resulting in elevated expression of the latter. CpG hypermethylation of miR-9-3 has been correlated with human cancer [9]. The Table 1 presents the SFN-regulated miRNAs in various research articles presented in this review.

In general, SFN appears to upregulate tumor suppressor miRNAs and downregulate oncomiRs in cancer (Fig. 3c). This is achieved by controlling the methylation of miRNA promoters.

Other epigenetic mechanisms regulated by Sulforaphane

Polycomb group (PcG) proteins are other epigenetic regulators that ensure histone methylation leading to chromatin compaction and gene inhibition. PcG proteins are highly present in cancer cells, resulting in a decrease of tumor suppressor proteins. Balasu et al. [38] displayed that SFN treatment results in a reduced expression of PcG proteins (Bmi-1, Ezh2) in skin cancer cells.

Sulforaphane indirectly modulates gene expression

Several studies have shown that SFN has the ability to modulate gene expression. In general, SFN increases the expression of tumor suppressor gene, at the same time it decreases the expression of oncogene. The mechanism of this modulation may be the demethylation of gene promoters via a decrease in DNMT, or chromatin decompaction via an increase in HAT, and a decrease in HDAC. Another possibility is the regulation of gene expression through miRNA. In all the cases, SFN appears to induce tumor suppressor genes and inhibit oncogenes mainly by epigenetic modulation.

In short, SFN acts first and foremost on epigenetic mechanisms by fixing the different aberrations. This correction indirectly activates tumor suppressor genes and inhibits oncogenes, leading to cell death and inhibition of cell proliferation (Fig. 4a and b).

Fig. 4.

Synthesis of SFN actions in cancer cells. a SFN inhibits HDACs and actives HATs leading chromatin decompaction. Chromatin accessible to transcription factors, tumor suppressor miRNAs and genes will be expressed; oncogenes and onco-miRNA will be inhibited. Tumor suppressor proteins induce cell cycle arrest and inhibition of cell proliferation. b SFN treats/prevents cancers by regulating epigenetic mechanisms (DNA methylation, HDAC expressions and changes in microRNA profile) resulting in tumor suppressor gene activation, oncogene silencing and leading to inhibition of cancer cells proliferation cells

SFN consumed during critical periods, also acts in long-term effect on cancer prevention

Certain stages of life, known as critical periods, play a major role in the development of cancer. These critical periods are characterized by fluctuations in hormone levels. For breast tissue, growth and development happen mainly during the prenatal, puberty and first pregnancy periods [48]. Brane et al. (2023) showed that the administration of broccoli sprouts during peripuberty period increased (in p21, p53 and BRCA2) gene expression and protein levels in HER2/neu mice. This administration also led to a diminution in the expression of 92 genes. In addition, there is an augmentation in the expresssion of 82 genes upregulated in the group treated with broccoli sprouts. Moreover, there is a growth in methylation level for 113 genes and a reduction in methylation rates for 130 genes in the broccoli sprouts group compared to the control group [48].

Li et al. [43] found that SFN and EGCG (epigallocatechin-3-gallate) inhibit tumors in mouse offspring via epigenetic regulation. Furthermore, studies point out that paternal and maternal treatment, particularly during gestation and lactation, with broccoli sprouts have some profound preventive effects on mammary cancer formation in the offspring mouse untreated [24, 53].

In summary, SFN administered alone or in combination at critical periods such as puberty and pregnancy, has the capacity to prevent cancer development in adulthood age and in offspring in vivo (mouse models).

Other health benefits of sulforaphane

SFN is non-toxic and bioavailable. It can also be excreted and absorbed by organisms [50, 65]. Among many health benefits of SFN (Fig. 5), we would like to mention a few : SFN has a beneficial effect on the microbiota [33], it is beneficial for muscular exercise [66]. It is an anti-diabetic agent [67–69]. It also helps protect people from cardiopulmonary disease [70, 71], nerve disease [72–74], and organ damage [75, 76]. It ameliorates blood pressure in a hypertensive pregnant women [77]. It is also known to be an antimicrobial agent, protecting from several infections [29, 78] and SARS-CoV-2 [79]. It also improves fertility [80, 81].

Fig. 5.

Health benefits of Sulforaphane. SFN is a powerful anticancer, antimicrobial, antidiabetic agent. It also modulates gastrointestinal microbiota, improves blood pressure in women with pregnancy hypertension, muscle activities and fertility, protects nervous system and fight against organs injuries and pulmonary diseases. Adapted by Dabré et al. (2024)

Conclusion

All in all, several studies have revealed that SFN has anticancer activities. It has the ability to correct epigenetic aberrations in cancer cells, destroy cancer cells. In this systematic review, we found that SFN induces apoptosis and cell cycle arrest, and decreases HDAC levels and increases histone acetylation, and can also control the methylation of miRNA promoters. We also remark that SFN (alone or in combination) being administered at the critical periods such as puberty and pregnancy, has the capability to avert the expansion of cancer in adulthood and in progenies. Further studies are needed to determine the best combination between SFN and other natural compounds in vitro and in vivo (mice models). Cohort studies are hence encouraged to determine any adverse and toxicity effects of regular SFN consumption.

Abbreviations

SFN

Sulforaphane

HAT

Histone acetyl transferase

HDAC

Histone deacetylase

DNMT

DNA methyltransferase

HDACI

Histone deacetylase inhibitor

DNMTI

DNA methyltransferase inhibitor

miRNA

MicroRNA

mRNA

Messenger RNA

4NQO

4-nitroquinoline-1-oxide

Author contributions

Conceptualization, AAZ and SD; Methodology, SD, AAZ, LB, JAK MS and ADT; Software, SD and MS; Validation, AAZ; Formal Analysis and investigation, SD, AAZ, LB and JAK; Writing – Review & Editing, SD and AAZ Visualization, LB, JAK, MS and ADT; Supervision, FD and JS. All authors were the major contributors in writing the manuscript. All authors read and approved the final manuscript.Funding: None Availability of data and materialsNot applicable.Competing interestsThe authors declare that they have no competing interests.

Funding

None.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Competing interests

The authors declare no competing interests.