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CANCER THERAPY
Table of Contents
CLASSES AND FUNCTIONS OF SIRTUINS.
THERAPEUTIC POTENTIALS OF SIRTUINs
ABSTRACT
The human race is facing many life-threatening diseases and it is highly important that these diseases are detected earlier so that they are eligible for a cure and medical treatment. Amongst these life-threatening diseases, the most common ones are cancers and tumours. A huge number of researches are being carried out in this area to save the human life from these fatal diseases. Over the past few years, it has been observed that sirtuins have played a dominant role in determining stress responses. There are studies showing that SIRT2 and SIRT6 have helped in suppressing tumours, however, some other sirtuins that include SIRT1 play a dual role that is, sometimes it acts as tumour suppressor and sometimes as oncogenic. The major goal of this essay is to highlight the roles of sirtuins and their potentials as novel targets in cancer therapy. However, several sirtuin inhibitors including nicotinamide, sirtinol have also proven useful in the treatment of cancerous diseases. In this essay, I have firstly highlighted all the classes of sirtuin and their functionality in order to explain the role of sirtuins in cancer therapy.
INTRODUCTION
Sirtuins, known as the silent information regulator 2 (SIRT) proteins, belong to Class III histone deacetylases (HDACs) that are highly conserved from bacteria to human (Kleszcz et al., 2015). There are seven members of sirtuins (SIRT1-7) that can be found in mammals which are localized in different cellular compartments for post-translational modification and possess different substrate specificities and functions. While SIRT1 is located in the nucleus and in the cytoplasm, SIRT2 is found in cytoplasm and SIRT3, SIRT4 and SIRT5 are predominantly present in mitochondria, whereas SIRT6 and SIRT7 are exclusively localized in the nucleus, these are shown in Figure 2. Unlike the Class I and II histone deacetylases, which utilise zinc as a cofactor, nicotine adenine dinucleotide (NAD+) is required for the sirtuins to catalyze two chemical reactions- deacetylation and ADP-ribosylation. SIRT1, SIRT2, SIRT3, SIRT5 and SIRT7 have been shown to catalyze deacetylation reaction of histones and non-histone proteins, resulting in the formation of deacetylating products, O-acetyl-ADP-ribose and nicotinamide. These two products are known to regulate sirtuins activities. Increasing the NAD+/NADH ratio can up-regulate the activities of sirtuins; on the other hand, increasing the nicotinamide levels can down-regulate these activities, suggesting that nicotinamide might have a role in the inhibition of sirtuins in vivo. In SIRT4 and SIRT6, the transferring of ADP-ribose portion from NAD+ to the substrates is catalyzed by ADP-ribosyl transferases during the ADP-ribosylation, yielding nicotinamide as the side-product. The roles of sirtuins have been studied and implicated in areas of neurodegenerative and cardiovascular diseases, inflammation, diabetes, and cancer.
CANCER THERAPY: Amongst the life-threatening diseases of the world, cancer lies on the top. In spite of the technological advancements and improved approaches to treating cancerous diseases, several shortcomings are observed.
The significant of the disease is highlighted by these observations and the importance of much-improved cancer therapies in order to enhance the efficiency of treatment. Therefore, it is highly important that new methods are developed, that can help in the regulation of various cancer processes and can turn useful in providing better treatments. The study of sirtuins (including SIRT1-7) has been proven useful in the treatment of cancer. In this essay, I will explore the role of sirtuins and their potential as a novel target for the treatment of cancer.
CLASSES AND FUNCTIONS OF SIRTUINS
Generally, most of the sirtuins act as tumour suppressors but there are some sirtuins that act as tumour activators, promoting cancer cell survival and angiogenesis. All mammalian sirtuins comprise a preserved catalytic core domain with 275 amino acids, but they are different in their N-and C-terminal extensions in terms of length and sequence. The structure shares a small zinc-binding domain and large Rossmann-fold domain typical for the attachment of NAD+ (Moniot et al., 2012, Figure 1).
Figure 1: Overall Structure of Sirtuins
All mammalian sirtuins have a pocket in between the zinc-binding domain and a large Rossmann-fold domain, for the binding of NAD+ and acetylated proteins during the chemical reactions. Targets of sirtuins include p53, FOXO, a-tubulin and other non-histone proteins. Taken from Moniot et al., 2012.
Sirtuin 1 (SIRT1)
SIRT1, a nuclear protein, is expressed in most mammalian tissues and has similar sequence and enzymatic activity to yeast Sir2. The role of SIRT1 in humans is still under debate and has been extensively researched due to its dual functions in cancer either by promoting or inhibiting cancer cell survival. SIRT1 mediates the process of deacetylation through the suppression of a variety of tumour suppressors including p53, p73, and HIC1; indicating SIRT1 has a role in promoting tumour enlargement over a period of time (Lin et al., 2013). SIRT1 is further divided in several types of cancer disease such as breast cancer, colon cancer, ovarian cancer, liver cancer, prostate cancer, glioblastoma, and bladder carcinoma (Chalkiadaki et al., 2015). On the other hand, SIRT1 may be oncogenic and increase its expression in liver cancer, colon cancer, as well as hematopoietic cancers when compared to normal tissues (Chalkiadaki et al., 2015). Also, high expression of SIRT1 had been found in prostate cancer tissues, compared with adjoining usual prostate tissues due to the deacetylation and inactivation of FOXO1 protein, by inhibiting apoptosis or shielding cells from oxidative stress and DNA damage (Jung-Hynes et al., 2009). The protein increased SIRT1 promotes cancer cells survival against apoptosis in various types of tissues by deacetylation of p53, BCL6, FOXO3a, and KU70 (Marshall et al., 2011).
Sirtuin 2 (SIRT2)
SIRT2, a histone deacetylase, is predominantly a cytoplasmic protein but it can sometime translocate into the nucleus. SIRT2 co-localizes with microtubules where it deacetylates the first known substrate of SIRT2- tubulin at Lys40 in both in vivo and in vitro (North et al., 2003)…
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