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      Targeting SREBP-2-Regulated Mevalonate Metabolism for Cancer Therapy

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          Abstract

          Recently, targeting metabolic reprogramming has emerged as a potential therapeutic approach for fighting cancer. Sterol regulatory element binding protein-2 (SREBP-2), a basic helix-loop-helix leucine zipper transcription factor, mainly regulates genes involved in cholesterol biosynthesis and homeostasis. SREBP-2 binds to the sterol regulatory elements (SREs) in the promoters of its target genes and activates the transcription of mevalonate pathway genes, such as HMG-CoA reductase (HMGCR), mevalonate kinase and other key enzymes. In this review, we first summarized the structure of SREBP-2 and its activation and regulation by multiple signaling pathways. We then found that SREBP-2 and its regulated enzymes, including HMGCR, FPPS, SQS, and DHCR4 from the mevalonate pathway, participate in the progression of various cancers, including prostate, breast, lung, and hepatocellular cancer, as potential targets. Importantly, preclinical and clinical research demonstrated that fatostatin, statins, and N-BPs targeting SREBP-2, HMGCR, and FPPS, respectively, alone or in combination with other drugs, have been used for the treatment of different cancers. This review summarizes new insights into the critical role of the SREBP-2-regulated mevalonate pathway for cancer and its potential for targeted cancer therapy.

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          Most cited references197

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          Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.

          The synthesis of fatty acids and cholesterol, the building blocks of membranes, is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs as a result of gene knockout of SREBP cleavage-activating protein (SCAP), a protein required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. A total of 1,003 genes showed statistically significant increased expression in livers of transgenic SREBP-1a mice, 505 increased in livers of transgenic SREBP-2 mice, and 343 showed decreased expression in Scap-/- livers. A subset of 33 genes met the stringent combinatorial criteria of induction in both SREBP transgenics and decreased expression in SCAP-deficient mice. Of these 33 genes, 13 were previously identified as direct targets of SREBP action. Of the remaining 20 genes, 13 encode enzymes or carrier proteins involved in cholesterol metabolism, 3 participate in fatty acid metabolism, and 4 have no known connection to lipid metabolism. Through application of stringent combinatorial criteria, the transgenic/knockout approach allows identification of genes whose activities are likely to be controlled directly by one family of transcription factors, in this case the SREBPs.
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            The Role of Cholesterol in Cancer.

            The roles played by cholesterol in cancer development and the potential of therapeutically targeting cholesterol homeostasis is a controversial area in the cancer community. Several epidemiologic studies report an association between cancer and serum cholesterol levels or statin use, while others suggest that there is not one. Furthermore, the Cancer Genome Atlas (TCGA) project using next-generation sequencing has profiled the mutational status and expression levels of all the genes in diverse cancers, including those involved in cholesterol metabolism, providing correlative support for a role of the cholesterol pathway in cancer development. Finally, preclinical studies tend to more consistently support the role of cholesterol in cancer, with several demonstrating that cholesterol homeostasis genes can modulate development. Because of space limitations, this review provides selected examples of the epidemiologic, TCGA, and preclinical data, focusing on alterations in cholesterol homeostasis and its consequent effect on patient survival. In melanoma, this focused analysis demonstrated that enhanced expression of cholesterol synthesis genes was associated with decreased patient survival. Collectively, the studies in melanoma and other cancer types suggested a potential role of disrupted cholesterol homeostasis in cancer development but additional studies are needed to link population-based epidemiological data, the TCGA database results, and preclinical mechanistic evidence to concretely resolve this controversy. Cancer Res; 76(8); 2063-70. ©2016 AACR.
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              Increased lipogenesis, induced by AKT-mTORC1-RPS6 signaling, promotes development of human hepatocellular carcinoma.

              De novo lipogenesis is believed to be involved in oncogenesis. We investigated the role of aberrant lipid biosynthesis in the pathogenesis of human hepatocellular carcinoma (HCC). We evaluated expression of enzymes that regulate lipogenesis in human normal liver tissues and HCC and surrounding, nontumor, liver tissues from patients using real-time reverse transcription polymerase chain reaction, immunoblotting, immunohistochemistry, and biochemical assays. Effects of lipogenic enzymes on human HCC cell lines were evaluated using inhibitors and overexpression experiments. The lipogenic role of the proto-oncogene AKT was assessed in vitro and in vivo. In human liver samples, de novo lipogenesis was progressively induced from nontumorous liver tissue toward the HCC. Extent of aberrant lipogenesis correlated with clinical aggressiveness, activation of the AKT-mammalian target of rapamycin signaling pathway, and suppression of adenosine monophosphate-activated protein kinases. In HCC cell lines, the AKT-mammalian target of rapamycin complex 1-ribosomal protein S6 pathway promoted lipogenesis via transcriptional and post-transcriptional mechanisms that included inhibition of fatty acid synthase ubiquitination by the USP2a de-ubiquitinase and disruption of the SREBP1 and SREBP2 degradation complexes. Suppression of the genes adenosine triphosphate citrate lyase, acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, or sterol regulatory element-binding protein 1, which are involved in lipogenesis, reduced proliferation, and survival of HCC cell lines and AKT-dependent cell proliferation. Overexpression of an activated form of AKT in livers of mice induced lipogenesis and tumor development. De novo lipogenesis has pathogenic and prognostic significance for HCC. Inhibitors of lipogenic signaling, including those that inhibit the AKT pathway, might be useful as therapeutics for patients with liver cancer. Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                21 August 2020
                2020
                : 10
                : 1510
                Affiliations
                [1] 1Research Center of Traditional Chinese Medicine, College of Traditional Chinese Medicine, Changchun University of Chinese Medicine , Changchun, China
                [2] 2Key Laboratory of Active Substances and Biological Mechanisms of Ginseng Efficacy, Ministry of Education, Jilin Provincial Key Laboratory of Bio-Macromolecules of Chinese Medicine, Jilin Ginseng Academy, Changchun University of Chinese Medicine , Changchun, China
                [3] 3College of Traditional Chinese Medicine, Changchun University of Chinese Medicine , Changchun, China
                [4] 4Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University , Spokane, WA, United States
                Author notes

                Edited by: Miriam Martini, University of Turin, Italy

                Reviewed by: Cinzia Domenicotti, University of Genoa, Italy; Paola Defilippi, University of Turin, Italy

                *Correspondence: Boyang Jason Wu boyang.wu@ 123456wsu.edu

                This article was submitted to Cancer Metabolism, a section of the journal Frontiers in Oncology

                Article
                10.3389/fonc.2020.01510
                7472741
                32974183
                fbca44d2-ebf8-47e7-a4d8-16c3522cebc8
                Copyright © 2020 Xue, Qi, Zhang, Ding, Huang, Zhao, Wu and Li.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 April 2020
                : 14 July 2020
                Page count
                Figures: 2, Tables: 3, Equations: 0, References: 233, Pages: 20, Words: 16476
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81602257
                Funded by: Jilin Scientific and Technological Development Program 10.13039/501100013061
                Award ID: 20190101010JH
                Categories
                Oncology
                Review

                Oncology & Radiotherapy
                srebp-2,hmg-coa reductase,mevalonate,cholesterol,cancer therapy
                Oncology & Radiotherapy
                srebp-2, hmg-coa reductase, mevalonate, cholesterol, cancer therapy

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