Anticancer Activity of Sulforaphane: The Epigenetic Mechanisms and the Nrf2 Signaling Pathway

Oxidative Medicine and Cellular Longevity, Jun 2018

Sulforaphane (SFN), a compound derived from cruciferous vegetables that has been shown to be safe and nontoxic, with minimal/no side effects, has been extensively studied due to its numerous bioactivities, such as anticancer and antioxidant activities. SFN exerts its anticancer effects by modulating key signaling pathways and genes involved in the induction of apoptosis, cell cycle arrest, and inhibition of angiogenesis. SFN also upregulates a series of cytoprotective genes by activating nuclear factor erythroid-2- (NF-E2-) related factor 2 (Nrf2), a critical transcription factor activated in response to oxidative stress; Nrf2 activation is also involved in the cancer-preventive effects of SFN. Accumulating evidence supports that epigenetic modification is an important factor in carcinogenesis and cancer progression, as epigenetic alterations often contribute to the inhibition of tumor-suppressor genes and the activation of oncogenes, which enables cells to acquire cancer-promoting properties. Studies on the mechanisms underlying the anticancer effects of SFN have shown that SFN can reverse such epigenetic alterations in cancers by targeting DNA methyltransferases (DNMTs), histone deacetyltransferases (HDACs), and noncoding RNAs. Therefore, in this review, we will discuss the anticancer activities of SFN and its mechanisms, with a particular emphasis on epigenetic modifications, including epigenetic reactivation of Nrf2.

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Anticancer Activity of Sulforaphane: The Epigenetic Mechanisms and the Nrf2 Signaling Pathway

Anticancer Activity of Sulforaphane: The Epigenetic Mechanisms and the Nrf2 Signaling Pathway Xuling Su,1 Xin Jiang,2 Lingbin Meng,3 Xiaoming Dong,1 Yanjun Shen,4 and Ying Xin1 1Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China 2Department of Radiation Oncology, The First Hospital of Jilin University, Changchun, China 3Department of Internal Medicine, Florida Hospital, Orlando, FL, USA 4Department of Pathology, Shanxi Medical University, Taiyuan, China Correspondence should be addressed to Ying Xin; nc.ude.ulj@ynix Received 22 January 2018; Revised 27 April 2018; Accepted 8 May 2018; Published 6 June 2018 Academic Editor: Sharad S. Singhal Copyright © 2018 Xuling Su et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract Sulforaphane (SFN), a compound derived from cruciferous vegetables that has been shown to be safe and nontoxic, with minimal/no side effects, has been extensively studied due to its numerous bioactivities, such as anticancer and antioxidant activities. SFN exerts its anticancer effects by modulating key signaling pathways and genes involved in the induction of apoptosis, cell cycle arrest, and inhibition of angiogenesis. SFN also upregulates a series of cytoprotective genes by activating nuclear factor erythroid-2- (NF-E2-) related factor 2 (Nrf2), a critical transcription factor activated in response to oxidative stress; Nrf2 activation is also involved in the cancer-preventive effects of SFN. Accumulating evidence supports that epigenetic modification is an important factor in carcinogenesis and cancer progression, as epigenetic alterations often contribute to the inhibition of tumor-suppressor genes and the activation of oncogenes, which enables cells to acquire cancer-promoting properties. Studies on the mechanisms underlying the anticancer effects of SFN have shown that SFN can reverse such epigenetic alterations in cancers by targeting DNA methyltransferases (DNMTs), histone deacetyltransferases (HDACs), and noncoding RNAs. Therefore, in this review, we will discuss the anticancer activities of SFN and its mechanisms, with a particular emphasis on epigenetic modifications, including epigenetic reactivation of Nrf2. 1. Introduction Numerous studies have suggested that high dietary intake of cruciferous vegetables is correlated with a low risk of cancer [1]. The anticancer activity of cruciferous vegetables has been mainly attributed to isothiocyanates, which are a product of myrosinase-mediated glucosinolate degradation. Sulforaphane (SFN) is a naturally occurring isothiocyanate derived from the consumption of cruciferous vegetables, such as broccoli, cabbage, and kale. Because of its efficacy, safety, nontoxicity, lack of side effects, and low cost, bioactive SFN is widely recognized as a promising chemopreventive agent with effects against many kinds of cancers, such as cervical [2], breast [3], and bladder cancer [4]; renal cell carcinoma (RCC) [5]; non-small-cell lung cancer (NSCLC) [6]; and colon and prostate cancers [7]. SFN has also been reported to improve the efficacy of low-dose cisplatin (CDDP), a commonly used chemotherapeutic drug [8]. Studies on the mechanisms underlying the anticancer activities of SFN indicate that its regulatory effects on the tumor cell cycle, apoptosis, and angiogenesis are mediated by modulation of the related signaling pathways and genes. Cell cycle analysis showed that SFN caused G2/M phase arrest leading to inhibition of tumor proliferation/growth, which was associated with downregulation of cyclin B1 [2] and cyclin D1 genes [9], as well as increased protein levels of p21WAF1/CIP1 (an inhibitor of cyclin-dependent kinases) [9]. SFN also increased the expression of the proapoptotic protein Bax and decreased expression of the antiapoptotic protein Bcl-x to induce apoptosis in cancer cells [10]. By suppressing the expression and activity of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF), SFN inhibited the angiogenesis and metastasis of ovarian and colon cancers [11, 12]. SFN was also reported to be a strong activator of nuclear factor erythroid-2 (NF-E2-) related factor 2 (Nrf2). It is well known that long-term exposure to oxidative stress is an important carcinogenesis-promoting factor that induces DNA damage, mutations, and inflammation [13]. Nrf2 is a critical transcription factor in the antioxidant stress response. Activation of Nrf2 by SFN induced the expression of a battery of cytoprotective genes with anticarcinogenesis activities [14–16]. Those Nrf2-mediated cytoprotective genes include the antioxidants and phase II enzymes, such as NAD(P)H:quinone oxidoreductase-1 (NQO1), heme oxygenase 1 (HO-1), catalase, glutamate-cysteine ligase (GCL), glutathione S transferase (GST), UDP-glucurono (...truncated)


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Xuling Su, Xin Jiang, Lingbin Meng, Xiaoming Dong, Yanjun Shen, Ying Xin. Anticancer Activity of Sulforaphane: The Epigenetic Mechanisms and the Nrf2 Signaling Pathway, Oxidative Medicine and Cellular Longevity, 2018, 2018, DOI: 10.1155/2018/5438179