Let's find out how the cruciferous vegetable Broccoli aids in epigenetic modulation and guards our DNA!!!
Abstract
Presently epigenetics is becoming one of the most researched fields around the globe, its role in curing various types of cancers has helped scientists for better treatment. It is the study of DNA, and how the environment and diet can also affect our genes leading to the formation of tumors. Sulforaphane (SFN) is a dietary isothiocyanate compound found in broccoli, brussels sprouts, kale, cabbage, and other cruciferous vegetables. These SFN are very effective in controlling carcinogenesis, they kind of modulate the cancerous cells and inhibit their mechanisms and growth in the tissues. Sulforaphane shows antioxidant, antitumor, anti-inflammatory, antimicrobial activities, inhibits angiogenesis and can regulate the cell cycle. The presence of many vitamins, sulfides, antioxidants, and glucosinolates in broccoli makes it an important part of our diet, thus getting the title as “Green chemoprevention”. It can cure breast, colon, skin, urinary bladder, and oral cancers and is much more effective than commercially available pills and drugs.
Figure 1: Broccoli, the cruciferous vegetable
Introduction
Cancers are not only caused by genetic disorders but also by epigenetic changes that induce tumor formation, so preventive measures can be taken to control them. Sulforaphane (1-isothiocyanato-4-[methylsulfinyl] butane) compound was discovered by Paul Talalay, it is a phytochemical synthesized from a precursor found in cruciferous vegetables of the genus Brassica. The enzymes of this family can suppress and alter the functions of genes that cause tumors. SFN was first reported to inhibit histone deacetylase (HDAC) in the human colon cancer cells, its continuous supply caused an increase in acetylated histones and helped in suppressing tumor growth in the cells. Researchers in the Linus Pauling Institute at Oregon State University have found another function of SFN to prevent cancer by DNA methylation and has proven to suppress the expression of genes, also helps in microRNA modulation by the selective killing of the cancerous cell. Broccoli contains an enzyme called Myrosinase which helps in hydrolyzing SFN to isothiocyanates from glucosinolates and is also responsible for the reduced production of SFN through the inactivation process. Myrosinase can be hydrolyzed by heating or boiling to an extreme level and destroys the anticancer property, so it is good to eat raw broccoli as it would preserve the enzymes. Sulforaphane is absorbed in the jejunum and then transported to the cells, helping in removing unwanted metabolites through the kidney.
Figure 2: conversion of glucoraphanin into sulphrophane by myrosinase.
Histone Deacetylases ( HDACs) and SFN as Histone Deacetylase Inhibitor (HDI):
Post-translational modification of histone proteins (mainly acetylation/deacetylation) is important in the formation of chromatin structure. Histones get acetylated by histone acetyltransferases (HATs) that convert the positive charge on lysine to neutral charge, resulting in dissociation of histone proteins with the negatively charged DNA. Thus the DNA gets opened up for transcriptional processes. Histone deacetylation is the process catalyzed by histone deacetylases (HDACs), in which the acetyl groups are removed from the lysine and cause condensation of chromosomes. This tightly packed chromosome is responsible for the inactivation of tumor-suppressing genes, many cancers develop because of increased activity of histone deacetylases.
Synthetic Histone Deacetylase Inhibitors (HDIs), like trichostatin A (TSA), SAHA, and valproic acid can inhibit deacetylation and are dependent on the concentration used to cure a particular cancer cell line.
For example, human colon cancer can be cured by 24hr treatment with TSA which increased histone acetylation and re-expression of RAR2. The use of these synthetic HDIs shows several side effects such as developmental abnormalities and neural defects, etc., and can be toxic to several patients, so naturally available HDI is found and sulforaphane is one of them.
SFN and its metabolites obtained from mercapturic acid pathways act as HDI. They inhibit the activity of HDAC by interacting with the external amino acid residues present on the active site. Invitro and invivo experiments prove that SFN concentration of 15µM can inhibit HDACs by 30%-40% and increase acetylation by 50%-100%, causing apoptosis of cancerous cells. For example, when SFN was given for 21 days at a dose of 7.5µmol resulted in a 40% reduction of prostate cancer in mice.
DNA methylation by SFN:
Scientists suggest that chromatin condensation is one of the reasons for changes in DNA methylation processes. Research says that there is a strong interdependence between DNA methylation, histone deacetylation, and chromosome condensation. DNA methylation is the process of silencing the transcriptional domain of the DNA and is maintained by DNA methyltransferases (DNMTs), its interaction with MBP protein (binding methylated sequences CpG) silences the gene activity and provides a signal for histone deacetylation.
These DNA modifications are readily reversible through epigenetic changes (environment, diet, and physiological factors) and the activity of the silenced genes can be regained only in the presence of DNA methyltransferase inhibitors. An increase in DNMTs/hypermethylation can induce cancer in the cells as they would silence the tumor-suppressing genes, thus their regulation is important for anticancer therapy. Treatment with HDIs can remove DNMTs from the replication site and cause hypomethylation of genes responsible for cell cycle regulation and tumor suppression.
As studies on SFN influencing DNA methylation are going on, it is found that SFN can increase the expression of genes with unmethylated promoters, but isothiocyanate is not much effective in decreasing hypermethylation. Studies and results show that when SFN is given for 48hr with a dose of 30µM, it can down-regulate DNMTs and de-repress methylation silenced cyclin D2 expression. Due to which cells get regulated and tumor-suppressing genes get activated.
Various Roles/Functions of SFN in preventing cancers:
Studies on sulforaphane as an anticancer remedy are going on, proving its efficiency and mechanism.
Significant inhibition of DNMTs is observed with the help of SFN when given to breast cancer patients.
SFN is a potent HDAC inhibitor and helps in suppressing human telomerase reverse transcriptase (hTERT) via epigenetic modulation.
SFN helps in chromatin remodeling and affects histone methylation in gene expression.
Ultraviolet lights which cause skin cancer and melanoma are prevented by SFN.
Selective killing of tumor cells makes SFN an important compound in curing cancer, it can cause autophagy in cancer cells.
SFN inhibits the development of new blood vessels and prevents the growth of tumor cells.
SFN can prevent Cancer Stem Cells (CSCs) which are responsible for maintaining cancer in our body.
It exhibits neuroprotective effects and helps in treating brain injury, Parkinson’s disease, etc.
Conclusion
Consuming cruciferous vegetables like broccoli, which contains bioactive isothiocyanate helps to prevent the development of cancer and also protects us from hazardous molecules that damage our DNA. The process of isothiocyanate formation is carried out by the myrosinase enzyme whose activity is increased by chewing and chopping vegetables. Sulforaphane plays an important role in the reactivation and re-expression of genes, thus SFN helps in activating the tumor suppressor genes and controls the growth of cancer in our body. Broccoli contains enough Vitamin A and fibers helping in the digestion and maintenance of our health. Overconsumption of broccoli has side effects which include diarrhea, bowel syndrome, gastric irritation, etc.
So adding broccoli to your diet keeps you healthy, fit and reduces the risk of cancer!
Daniya M Raju
Dept. of Biochemistry & Biotechnology
St Xavier's college.
References
Kaufman-Szymczyk, A., Majewski, G., Lubecka-Pietruszewska, K., & Fabianowska-Majewska, K. (2015). The Role of Sulforaphane in Epigenetic Mechanisms, Including Interdependence between Histone Modification and DNA Methylation. International journal of molecular sciences, 16(12), 29732–29743. https://doi.org/10.3390/ijms161226195
“role in cancer prevention.” researchgate, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068201/.
Oregon State University. (2012, February 28). Eat your broccoli: Another mechanism discovered by which sulforaphane prevents cancer. ScienceDaily. Retrieved July 9, 2021 from www.sciencedaily.com/releases/2012/02/120228140555.htm
(PDF) Sulforaphane in broccoli: The green chemoprevention!! Role in cancer prevention and therapy (“role in cancer prevention”)
https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/sulforaphane
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