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DNA Methylation Modifier LSH Inhibits P53 Ubiquitination And Chen et al. Epigenetics & Chromatin (2019) 12:59 https://doi.org/10.1186/s13072-019-0302-9 Epigenetics & Chromatin RESEARCH Open Access DNA methylation modifer LSH inhibits p53 ubiquitination and transactivates p53 to promote lipid metabolism Ling Chen1,2,3,8, Ying Shi1,2, Na Liu1,2, Zuli Wang1,2, Rui Yang1,2, Bin Yan1,2,4, Xiaoli Liu1,2, Weiwei Lai1,2, Yating Liu1,2, Desheng Xiao5, Hu Zhou6, Yan Cheng7, Ya Cao1,2, Shuang Liu4, Zanxian Xia8,9* and Yongguang Tao1,2,3,4,5* Abstract Background: The stability of p53 is mainly controlled by ubiquitin-dependent degradation, which is triggered by the E3 ubiquitin ligase MDM2. The chromatin modifer lymphoid-specifc helicase (LSH) is essential for DNA methyla- tion and cancer progression as a transcriptional repressor. The potential interplay between chromatin modifers and transcription factors remains largely unknown. Results: Here, we present data suggesting that LSH regulates p53 in cis through two pathways: prevention protea- somal degradation through its deubiquitination, which is achieved by reducing the lysine 11-linked, lysine 48-linked polyubiquitin chains (K11 and K48) on p53; and revival of the transcriptional activity of p53 by forming a complex with PKM2 (pyruvate kinase 2). Furthermore, we confrmed that the LSH–PKM2 interaction occurred at the intersubunit interface region of the PKM2 C-terminal region and the coiled-coil domains (CC) and ATP-binding domains of LSH, and this interaction regulated p53-mediated transactivation in cis in lipid metabolism, especially lipid catabolism. Conclusion: These fndings suggest that LSH is a novel regulator of p53 through the proteasomal pathway, thereby providing an alternative mechanism of p53 involvement in lipid metabolism in cancer. Keywords: LSH, P53, DUB, PKM2, Lipid metabolism Background decreasing fatty acid synthesis and increasing fatty acid Cancer cells are metabolically reprogrammed to help degradation [4–6]. them survive in malnourished environments, and Epigenetic alterations are increasingly implicated in strengthened proliferation and enhanced survival are cancer causation and progression, because chromatin common characteristics of cancer cells. In fact, changes functions in both the transcriptional regulation and the in glucose and glutamine metabolism are very impor- stability of genome [7, 8]. Furthermore, epigenetic abnor- tant for the development of tumors [1]. In recent years, malities are regarded as a hallmark of cancer, and com- increasing attention has been paid to the reprogramming monly studied mechanisms include DNA methylation of lipid metabolism that occurs in cancer cells [2, 3]. p53 and associated DNA methyltransferases [9, 10]. For this is a transcription factor controlling cellular metabo- reason, specifc chromatin-modifying enzymes have been lism, and it also plays a key role in tumor suppression by paid increasing attention in recent years, especially for they dynamically regulated histone modifcations [11]. For example, the levels of ubiquitylated and sumoylated *Correspondence: [email protected]; [email protected] 1 Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of H2A and p53 are upregulated in senescent cells, which of Education, Department of Pathology, Xiangya Hospital, Central South leads to proteasomal degradation [12]. In promyelocytic University, 87 Xiangya Road, Changsha 410008, Hunan, China leukemia (PML), sumoylation leads to senescence via a 8 Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, China complex interconnected network of pathways involved in Full list of author information is available at the end of the article the sumoylation of proteins. p53/pRb and its interacting © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chen et al. Epigenetics & Chromatin (2019) 12:59 Page 2 of 22 protein partners are engaged in senescence-specifc acti- maintains normal mammalian development by establish- vation [13]. ing correct levels of DNA methylation and maintaining p53 is a critical tumor suppressor that is mutated in genome stability [27–34]. LSH contributes to the malig- multiple kinds of human cancers, and it functions pri- nant progression of prostate cancer, melanoma, naso- marily as a transcription factor for genes involved in pharyngeal carcinoma, glioma, and non-small cell lung cellular senescence, energy metabolism, apoptosis, cell- cancer [9, 10, 32, 35–40], Interestingly, LSH might par- cycle progression, and other pathways that control cell ticipate in the regulation of cancer cell metabolism [38, fate [14, 15]. p53 protein levels are mainly regulated by 41, 42]. Clearly, LSH binding is involved in histone modi- ubiquitination/deubiquitination, an important post- fcation, DNA methylation, and chromatin accessibility, translational modifcation [16]. Ubiquitylation includes which are epigenetic events, and LSH-regulated epige- the covalent binding of ubiquitin residues to target pro- netic events are a dynamic process [43]. One question teins via the sequential actions of E1, E2, and E3 enzymes, arising from these studies is whether LSH might regulate which activate, conjugate, and connect ubiquitin, respec- protein modifcation. tively. Ubiquitin itself includes seven lysines, K6, K11, PKM2 is a key enzyme in glycolysis and catalyzes the K27, K29, K33, K48, and K63, and each lysine can be fnal step in glycolysis by catalyzing the dephosphoryla- conjugated to another at its carboxyl terminus, thereby tion of phosphoenolpyruvate (PEP) into pyruvate to gen- forming various types of polyubiquitin chains. For exam- erate ATP, playing a critical role in tumor metabolism and ple, K48-linked polyubiquitin chains are conjugated to serving as a potential diagnostic biomarker and therapeu- p53 by the RING-fnger E3 ligase mouse double minute tic target of tumors [44–46]. In addition, PKM2 localizes homolog2 (MDM2) and this modifcation results in p53 to the nucleus beyond its metabolic function, and nuclear degradation [17]; Tripartite motif-containing protein 45 PKM2 functions as a transcriptional coactivator of many (TRIM45) conjugates K63-linked polyubiquitin chain to genes [47, 48]. SIRT6 (sirtuin 6)-mediated deacetylation p53 C-terminal six lysine residues [18], and FATS-cata- of PKM2 suppresses nuclear transcriptional coactivator lyzed p53 polyubiquitination by K63-linked, K29-linked function of PKM2 [49]. PKM2, pyruvate dehydrogenase and K11-linked chains promotes p53 stabilization after complex (PDC), and histone acetyltransferase p300 form DNA damage [19]. a complex on chromatin with arylhydrocarbon receptor In contrast, deubiquitylases (DUBs) are enzymes that (AhR), and PKM2 works as a transcriptional coactiva- remove ubiquitin residues [20]. Multiple of ligases are tor that sensitizes AhR-mediated detoxifcation [50, 51]. involved in the ubiquitination reaction, and MDM2 is a PKM2 functions as a coactivator to enhance transactiva- crucial ubiquitin ligase that promotes the ubiquitination tion of hypoxia-inducible factor-1 (HIF-1) target genes by and degradation of p53, thereby preventing the induc- interacting directly with the HIF-1 α subunit [52]. Here, tion of p53 target genes. p53 ubiquitination by MDM2 we reveal the possibility that LSH is responsible for p53 and a great number of other E3 ubiquitin ligases, such activation during lipid metabolism, and PKM2 functions as CONSTITUTIVELY PHOTOMORPHOGENIC 1 as a coactivator. (COP1), Pirh2, and male-specifc-lethal-2 (MSL2), regu- lates its degradation [21]. When cells are under pressure, Results HAUSP and several other deubiquitinating enzymes, LSH does not alter the p53 mRNA level, but upregulates such as USP10, USP29 and USP42, can remove ubiquitin the protein level of p53 chains from p53, to induce p53 stabilization; the enzyme To address the potential role of LSH in p53 expres- can also act on other proteins, including MDM2 [22, 23]. sion, we stably overexpressed LSH in two cell lines, Upon DNA damage, p53 is induced by post-translational CNE1-FLAG-LSH and HK1-FLAG-LSH, and we modifcations, such as phosphorylation, which disrupt its found that LSH drastically promoted levels of endog- interaction with MDM2 and lead to its increased stabil- enous p53 and that p21, a target of p53, was induced ity of p53 [24]. MDM2-mediated ubiquitination of p53 by LSH in CNE1 and HK1 cells (Fig. 1a, b). To further enhances p53 degradation whereas the removal of ubiq- validate the role of LSH in p53 expression, we gener- uitin chains is regulated by deubiquitinating enzymes ated a stable knockdown of LSH in A549 lung cancer (DUBs). It is well acknowledged that there are approxi- cells. The knockdown approach successfully reduced mately 90 DUBs in the human proteome [25, 26]. How- LSH protein by more than 80% using two LSH-specific ever, the mechanisms regulating p53 deubiquitination short hairpin RNAs (shRNA#1 and shRNA#2), and we remain enigmatic. showed that stable knockdown of LSH dampened p53 LSH, also known as HELLS (helicase,
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