{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T03:05:18Z","timestamp":1789009518695,"version":"build-2803163510"},"reference-count":69,"publisher":"Springer Science and Business Media LLC","issue":"2","license":[{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T00:00:00Z","timestamp":1613088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"SRP14-VUB"},{"name":"the Hans von Kantzow Foundation"},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","award":["KDB 1335\/17"],"award-info":[{"award-number":["KDB 1335\/17"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","award":["CAN 2016\/458"],"award-info":[{"award-number":["CAN 2016\/458"]}],"id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Multiple myeloma (MM) is a heterogeneous haematological disease that remains clinically challenging. Increased activity of the epigenetic silencer EZH2 is a common feature in patients with poor prognosis. Previous findings have demonstrated that metabolic profiles can be sensitive markers for response to treatment in cancer. While EZH2 inhibition (EZH2i) has proven efficient in inducing cell death in a number of human MM cell lines, we hereby identified a subset of cell lines that despite a global loss of H3K27me3, remains viable after EZH2i. By coupling liquid chromatography-mass spectrometry with gene and miRNA expression profiling, we found that sensitivity to EZH2i correlated with distinct metabolic signatures resulting from a dysregulation of genes involved in methionine cycling. Specifically, EZH2i resulted in a miRNA-mediated downregulation of methionine cycling-associated genes in responsive cells. This induced metabolite accumulation and DNA damage, leading to G2 arrest and apoptosis. Altogether, we unveiled that sensitivity to EZH2i in human MM cell lines is associated with a specific metabolic and gene expression profile post-treatment.<\/jats:p>","DOI":"10.1038\/s41419-021-03447-8","type":"journal-article","created":{"date-parts":[[2021,2,12]],"date-time":"2021-02-12T08:05:40Z","timestamp":1613117140000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["A distinct metabolic response characterizes sensitivity to EZH2 inhibition in multiple myeloma"],"prefix":"10.1038","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1274-4010","authenticated-orcid":false,"given":"Patrick","family":"Nylund","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1872-0423","authenticated-orcid":false,"given":"Alba","family":"Atienza P\u00e1rraga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jakob","family":"Hagl\u00f6f","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4012-4617","authenticated-orcid":false,"given":"Elke","family":"De Bruyne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0805-6581","authenticated-orcid":false,"given":"Eline","family":"Menu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berta","family":"Garrido-Zabala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anqi","family":"Ma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2387-3862","authenticated-orcid":false,"given":"Jian","family":"Jin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fredrik","family":"\u00d6berg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Vanderkerken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4535-506X","authenticated-orcid":false,"given":"Antonia","family":"Kalushkova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9319-7986","authenticated-orcid":false,"given":"Helena","family":"Jernberg-Wiklund","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,2,12]]},"reference":[{"key":"3447_CR1","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/nrclinonc.2016.122","volume":"14","author":"S Manier","year":"2017","unstructured":"Manier, S. et al. Genomic complexity of multiple myeloma and its clinical implications. Nat. Rev. Clin. Oncol. 14, 100\u2013113 (2017).","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"3447_CR2","doi-asserted-by":"publisher","first-page":"413","DOI":"10.1007\/s10147-015-0837-0","volume":"20","author":"Y Furukawa","year":"2015","unstructured":"Furukawa, Y. & Kikuchi, J. Molecular pathogenesis of multiple myeloma. Int. J. Clin. Oncol. 20, 413\u2013422 (2015).","journal-title":"Int. J. Clin. Oncol."},{"key":"3447_CR3","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1038\/leu.2013.199","volume":"28","author":"BA Walker","year":"2014","unstructured":"Walker, B. A. et al. Intraclonal heterogeneity is a critical early event in the development of myeloma and precedes the development of clinical symptoms. Leukemia 28, 384\u2013390 (2014).","journal-title":"Leukemia"},{"key":"3447_CR4","doi-asserted-by":"publisher","first-page":"6809","DOI":"10.18632\/oncotarget.6843","volume":"7","author":"P Agarwal","year":"2016","unstructured":"Agarwal, P. et al. Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target. Oncotarget 7, 6809\u20136823 (2016).","journal-title":"Oncotarget"},{"key":"3447_CR5","doi-asserted-by":"publisher","first-page":"467","DOI":"10.1038\/nature09837","volume":"471","author":"MA Chapman","year":"2011","unstructured":"Chapman, M. A. et al. Initial genome sequencing and analysis of multiple myeloma. Nature 471, 467\u2013472 (2011).","journal-title":"Nature"},{"key":"3447_CR6","doi-asserted-by":"publisher","first-page":"3911","DOI":"10.1200\/JCO.2014.59.1503","volume":"33","author":"BA Walker","year":"2015","unstructured":"Walker, B. A. et al. Mutational spectrum, copy number changes, and outcome: results of a sequencing study of patients with newly diagnosed myeloma. J. Clin. Oncol. 33, 3911\u20133920 (2015).","journal-title":"J. Clin. Oncol."},{"key":"3447_CR7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011483","volume":"5","author":"A Kalushkova","year":"2010","unstructured":"Kalushkova, A. et al. Polycomb target genes are silenced in multiple myeloma. PLoS ONE 5, e11483 (2010).","journal-title":"PLoS ONE"},{"key":"3447_CR8","doi-asserted-by":"publisher","first-page":"1745","DOI":"10.1182\/blood.V99.5.1745","volume":"99","author":"F Zhan","year":"2002","unstructured":"Zhan, F. et al. Global gene expression profiling of multiple myeloma, monoclonal gammopathy of undetermined significance, and normal bone marrow plasma cells. Blood 99, 1745\u20131757 (2002).","journal-title":"Blood"},{"key":"3447_CR9","doi-asserted-by":"publisher","first-page":"6269","DOI":"10.1038\/sj.onc.1208771","volume":"24","author":"PA Croonquist","year":"2005","unstructured":"Croonquist, P. A. & Van Ness, B. The polycomb group protein enhancer of zeste homolog 2 (EZH2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype. Oncogene 24, 6269\u20136280 (2005).","journal-title":"Oncogene"},{"key":"3447_CR10","doi-asserted-by":"publisher","first-page":"2069","DOI":"10.1111\/cas.13326","volume":"108","author":"D Honma","year":"2017","unstructured":"Honma, D. et al. Novel orally bioavailable EZH1\/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 108, 2069\u20132078 (2017).","journal-title":"Cancer Sci."},{"key":"3447_CR11","doi-asserted-by":"publisher","first-page":"10213","DOI":"10.18632\/oncotarget.14378","volume":"8","author":"M Alzrigat","year":"2017","unstructured":"Alzrigat, M. et al. EZH2 inhibition in multiple myeloma downregulates myeloma associated oncogenes and upregulates microRNAs with potential tumor suppressor functions. Oncotarget 8, 10213\u201310224 (2017).","journal-title":"Oncotarget"},{"key":"3447_CR12","doi-asserted-by":"publisher","first-page":"4817","DOI":"10.1158\/1078-0432.CCR-16-2735","volume":"23","author":"O Rizq","year":"2017","unstructured":"Rizq, O. et al. Dual inhibition of EZH2 and EZH1 sensitizes PRC2-dependent tumors to proteasome inhibition. Clin. Cancer Res. 23, 4817\u20134830 (2017).","journal-title":"Clin. Cancer Res."},{"key":"3447_CR13","doi-asserted-by":"publisher","first-page":"2471","DOI":"10.1038\/s41375-018-0140-y","volume":"32","author":"N Rastgoo","year":"2018","unstructured":"Rastgoo, N., Pourabdollah, M., Abdi, J., Reece, D. & Chang, H. Dysregulation of EZH2\/miR-138 axis contributes to drug resistance in multiple myeloma by downregulating RBPMS. Leukemia 32, 2471\u20132482 (2018).","journal-title":"Leukemia"},{"key":"3447_CR14","doi-asserted-by":"publisher","first-page":"e4251","DOI":"10.1371\/journal.pone.0004251","volume":"4","author":"S Tiziani","year":"2009","unstructured":"Tiziani, S. et al. Metabolimic profiling of drug responses in acute myeloid leukemia cell lines. PLoS ONE 4, e4251 (2009).","journal-title":"PLoS ONE"},{"key":"3447_CR15","doi-asserted-by":"publisher","first-page":"44541","DOI":"10.1038\/srep44541","volume":"7","author":"V Lopes-Rodrigues","year":"2017","unstructured":"Lopes-Rodrigues, V. et al. Identification of the metabolic alterations associated with the multidrug resistant phenotype in cancer and their intercellular transfer mediated by extracellular vesicles. Sci. Rep. 7, 44541 (2017).","journal-title":"Sci. Rep."},{"key":"3447_CR16","doi-asserted-by":"publisher","first-page":"3359","DOI":"10.1038\/onc.2016.485","volume":"36","author":"CC Wong","year":"2017","unstructured":"Wong, C. C., Qian, Y. & Yu, J. Interplay between epigenetics and metabolism in oncogenesis: mechanisms and therapeutic approaches. Oncogene 36, 3359\u20133374 (2017).","journal-title":"Oncogene"},{"key":"3447_CR17","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1034\/j.1600-065X.2003.00035.x","volume":"194","author":"K Vanderkerken","year":"2003","unstructured":"Vanderkerken, K., Asosingh, K., Croucher, P. & Van Camp, B. Multiple myeloma biology: lessons from the 5TMM models. Immunol. Rev 194, 196\u2013206 (2003).","journal-title":"Immunol. Rev"},{"key":"3447_CR18","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1038\/sj.thj.6200052","volume":"1","author":"K Asosingh","year":"2000","unstructured":"Asosingh, K., Radl, J., Van Riet, I., Van Camp, B. & Vanderkerken, K. The 5TMM series: a useful in vivo mouse model of human multiple myeloma. Hematol. J. 1, 351\u2013356 (2000).","journal-title":"Hematol. J."},{"key":"3447_CR19","doi-asserted-by":"crossref","first-page":"609","DOI":"10.4049\/jimmunol.122.2.609","volume":"122","author":"J Zurcher","year":"1979","unstructured":"Zurcher, J. et al. Young C57BL\/KaLwRij Mice of the Paraprotein-Producing Clone from Old to Idiopathic Paraproteinemia: II. Transplantation IDIOPATHIC PARAPROTEINEMIA II. Transplantation of the Paraprotein-Producing Clone from Old to Young C57BL\/KaLwRij Mice. J. Immunol. 122, 609\u2013613 (1979).","journal-title":"J. Immunol."},{"key":"3447_CR20","doi-asserted-by":"publisher","first-page":"451","DOI":"10.1038\/bjc.1997.409","volume":"76","author":"K Vanderkerken","year":"1997","unstructured":"Vanderkerken, K. et al. Organ involvement and phenotypic adhesion profile of 5T2 and 5T33 myeloma cells in the C57BL\/KaLwRij mouse. Br. J. Cancer 76, 451\u2013460 (1997).","journal-title":"Br. J. Cancer"},{"key":"3447_CR21","doi-asserted-by":"publisher","first-page":"W486","DOI":"10.1093\/nar\/gky310","volume":"46","author":"J Chong","year":"2018","unstructured":"Chong, J. et al. MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis. Nucleic Acids Res 46, W486\u2013W494 (2018).","journal-title":"Nucleic Acids Res"},{"key":"3447_CR22","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1038\/sj.onc.1208447","volume":"24","author":"M Mattioli","year":"2005","unstructured":"Mattioli, M. et al. Gene expression profiling of plasma cell dyscrasias reveals molecular patterns associated with distinct IGH translocations in multiple myeloma. Oncogene 24, 2461\u20132473 (2005).","journal-title":"Oncogene"},{"key":"3447_CR23","doi-asserted-by":"publisher","first-page":"1692","DOI":"10.1182\/blood-2006-07-037077","volume":"109","author":"F Zhan","year":"2007","unstructured":"Zhan, F. et al. Gene-expression signature of benign monoclonal gammopathy evident in multiple myeloma is linked to good prognosis. Blood 109, 1692\u20131700 (2007).","journal-title":"Blood"},{"key":"3447_CR24","doi-asserted-by":"publisher","first-page":"3177","DOI":"10.1182\/blood-2006-09-044974","volume":"109","author":"G Mulligan","year":"2007","unstructured":"Mulligan, G. et al. Gene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor bortezomib. Blood 109, 3177\u20133188 (2007).","journal-title":"Blood"},{"key":"3447_CR25","doi-asserted-by":"publisher","first-page":"e05005","DOI":"10.7554\/eLife.05005","volume":"4","author":"V Agarwal","year":"2015","unstructured":"Agarwal, V., Bell, G. W., Nam, J. W. & Bartel, D. P. Predicting effective microRNA target sites in mammalian mRNAs. Elife 4, e05005 (2015).","journal-title":"Elife"},{"key":"3447_CR26","doi-asserted-by":"publisher","first-page":"3530","DOI":"10.1038\/sj.onc.1206440","volume":"22","author":"S Oikawa","year":"2003","unstructured":"Oikawa, S., Murakami, K. & Kawanishi, S. Oxidative damage to cellular and isolated DNA by homocysteine: implications for carcinogenesis. Oncogene 22, 3530\u20133538 (2003).","journal-title":"Oncogene"},{"key":"3447_CR27","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.gene.2014.02.015","volume":"539","author":"CS Vanzin","year":"2014","unstructured":"Vanzin, C. S. et al. Homocysteine contribution to DNA damage in cystathionine \u00e1-synthase-deficient patients. Gene 539, 270\u2013274 (2014).","journal-title":"Gene"},{"key":"3447_CR28","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1186\/s13045-020-00937-8","volume":"13","author":"R Duan","year":"2020","unstructured":"Duan, R., Du, W. & Guo, W. EZH2: a novel target for cancer treatment. J. Hematol. Oncol. 13, 104 (2020).","journal-title":"J. Hematol. Oncol."},{"key":"3447_CR29","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1021\/cb400133j","volume":"8","author":"KD Konze","year":"2013","unstructured":"Konze, K. D. et al. An orally bioavailable chemical probe of the lysine methyltransferases EZH2 and EZH1. ACS Chem. Biol. 8, 1324\u20131334 (2013).","journal-title":"ACS Chem. Biol."},{"key":"3447_CR30","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1158\/1535-7163.MCT-15-0486","volume":"15","author":"H Hernando","year":"2016","unstructured":"Hernando, H. et al. EZH2 inhibition blocks multiple myeloma cell growth through upregulation of epithelial tumor suppressor genes. Mol Cancer Ther 15, 287\u2013298 (2016).","journal-title":"Mol Cancer Ther"},{"key":"3447_CR31","doi-asserted-by":"publisher","first-page":"628","DOI":"10.1016\/j.celrep.2017.09.078","volume":"21","author":"T Ezponda","year":"2017","unstructured":"Ezponda, T. et al. UTX\/KDM6A loss enhances the malignant phenotype of multiple myeloma and sensitizes cells to EZH2 inhibition. Cell Rep 21, 628\u2013640 (2017).","journal-title":"Cell Rep"},{"key":"3447_CR32","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1182\/blood-2017-08-804344","volume":"131","author":"M Bisserier","year":"2018","unstructured":"Bisserier, M. & Wajapeyee, N. Mechanisms of resistance to ezh2 inhibitors in diffuse large b-cell lymphomas. Blood 131, 2125\u20132137 (2018).","journal-title":"Blood"},{"key":"3447_CR33","doi-asserted-by":"publisher","first-page":"1430","DOI":"10.3892\/or.2017.5430","volume":"37","author":"T Tao","year":"2017","unstructured":"Tao, T. et al. Involvement of EZH2 in aerobic glycolysis of prostate cancer through miR-181b\/HK2 axis. Oncol. Rep 37, 1430\u20131436 (2017).","journal-title":"Oncol. Rep"},{"key":"3447_CR34","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1111\/jnc.14152","volume":"143","author":"F Ahmad","year":"2017","unstructured":"Ahmad, F. et al. Telomerase reverse transcriptase (TERT) - enhancer of zeste homolog 2 (EZH2) network regulates lipid metabolism and DNA damage responses in glioblastoma. J. Neurochem. 143, 671\u2013683 (2017).","journal-title":"J. Neurochem."},{"key":"3447_CR35","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/j.jpha.2015.05.004","volume":"5","author":"XH Zheng","year":"2015","unstructured":"Zheng, X. H., Jiang, L. Y., Zhao, L. T., Zhang, Q. Y. & Ding, L. Simultaneous quantitation of folic acid and 5-methyltetrahydrofolic acid in human plasma by HPLC-MS\/MS and its application to a pharmacokinetic study. J. Pharm. Anal. 5, 269\u2013275 (2015).","journal-title":"J. Pharm. Anal."},{"key":"3447_CR36","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1111\/bjh.12152","volume":"160","author":"R Rosovsky","year":"2013","unstructured":"Rosovsky, R. et al. Endothelial stress products and coagulation markers in patients with multiple myeloma treated with lenalidomide plus dexamethasone: an observational study. Br. J. Haematol. 160, 351\u2013358 (2013).","journal-title":"Br. J. Haematol."},{"key":"3447_CR37","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1038\/s41591-019-0423-5","volume":"25","author":"Z Wang","year":"2019","unstructured":"Wang, Z. et al. Methionine is a metabolic dependency of tumor-initiating cells. Nat. Med 25, 825\u2013837 (2019).","journal-title":"Nat. Med"},{"key":"3447_CR38","doi-asserted-by":"publisher","first-page":"5741","DOI":"10.1158\/0008-5472.CAN-16-3480","volume":"77","author":"CM Phillips","year":"2017","unstructured":"Phillips, C. M. et al. Upregulation of cystathionine-\u03b2-synthase in colonic epithelia reprograms metabolism and promotes carcinogenesis. Cancer Res. 77, 5741\u20135754 (2017).","journal-title":"Cancer Res."},{"key":"3447_CR39","doi-asserted-by":"publisher","first-page":"49451","DOI":"10.18632\/oncotarget.17706","volume":"8","author":"S Salati","year":"2017","unstructured":"Salati, S. et al. Deregulated expression of miR-29a-3p, miR-494-3p and miR-660-5p affects sensitivity to tyrosine kinase inhibitors in CML leukemic stem cells. Oncotarget 8, 49451\u201349469 (2017).","journal-title":"Oncotarget"},{"key":"3447_CR40","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1002\/jcp.25628","volume":"232","author":"C Tian","year":"2017","unstructured":"Tian, C. et al. MicroRNA-494 activation suppresses bone marrow stromal cell-mediated drug resistance in acute myeloid leukemia cells. J. Cell Physiol. 232, 1387\u20131395 (2017).","journal-title":"J. Cell Physiol."},{"key":"3447_CR41","doi-asserted-by":"publisher","first-page":"506","DOI":"10.1016\/j.ccr.2012.09.003","volume":"22","author":"X Zhang","year":"2012","unstructured":"Zhang, X. et al. Coordinated silencing of MYC-mediated miR-29 by HDAC3 and EZH2 as a therapeutic target of histone modification in aggressive B-cell lymphomas. Cancer Cell 22, 506\u2013523 (2012).","journal-title":"Cancer Cell"},{"key":"3447_CR42","doi-asserted-by":"publisher","first-page":"1391","DOI":"10.7314\/APJCP.2014.15.3.1391","volume":"15","author":"YM Zhou","year":"2014","unstructured":"Zhou, Y. M., Liu, J. & Sun, W. MiR-130a overcomes gefitinib resistance by targeting met in non-small cell lung cancer cell lines. Asian Pacific J. Cancer Prev 15, 1391\u20131396 (2014).","journal-title":"Asian Pacific J. Cancer Prev"},{"key":"3447_CR43","doi-asserted-by":"publisher","first-page":"1568","DOI":"10.1002\/pros.23031","volume":"75","author":"Y Fujita","year":"2015","unstructured":"Fujita, Y. et al. MIR-130a activates apoptotic signaling through activation of caspase-8 in taxane-resistant prostate cancer cells. Prostate 75, 1568\u20131578 (2015).","journal-title":"Prostate"},{"key":"3447_CR44","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1002\/jcp.28957","volume":"23","author":"H Sun","year":"2020","unstructured":"Sun, H., Fan, G., Deng, C. & Wu, L. miR-4429 sensitized cervical cancer cells to irradiation by targeting RAD51. J. Cell. Physiol. 23, 185\u2013193 (2020).","journal-title":"J. Cell. Physiol."},{"key":"3447_CR45","doi-asserted-by":"publisher","first-page":"3141","DOI":"10.2147\/OTT.S143465","volume":"11","author":"K Chen","year":"2018","unstructured":"Chen, K. et al. miR-134 increases the antitumor effects of cytarabine by targeting Mnks in acute myeloid leukemia cells. Onco Targets Ther 11, 3141\u20133147 (2018).","journal-title":"Onco Targets Ther"},{"key":"3447_CR46","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3233\/CBM-170657","volume":"22","author":"C Tian","year":"2018","unstructured":"Tian, C. et al. Low miR-192 expression predicts poor prognosis in pediatric acute myeloid leukemia. Cancer Biomark. 22, 209\u2013215 (2018).","journal-title":"Cancer Biomark."},{"key":"3447_CR47","doi-asserted-by":"publisher","first-page":"e114647","DOI":"10.1371\/journal.pone.0114647","volume":"9","author":"Y Sun","year":"2014","unstructured":"Sun, Y., Pan, J., Mao, S. & Jin, J. IL-17\/miR-192\/IL-17Rs regulatory feedback loop facilitates multiple myeloma progression. PLoS ONE 9, e114647 (2014).","journal-title":"PLoS ONE"},{"key":"3447_CR48","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.ccell.2016.07.007","volume":"30","author":"F Pichiorri","year":"2016","unstructured":"Pichiorri, F. et al. Erratum: Downregulation of p53-inducible microRNAs 192, 194, and 215 Impairs the p53\/MDM2 Autoregulatory Loop in Multiple Myeloma Development (Cancer Cell (2010) 18(4) (367\u2013381) (S1535610810003429) (10.1016\/j.ccr.2010.09.005)). Cancer Cell. 30, 349\u2013351 (2016).","journal-title":"Cancer Cell."},{"key":"3447_CR49","doi-asserted-by":"publisher","first-page":"2811","DOI":"10.1093\/jn\/131.11.2811","volume":"131","author":"MA Caudill","year":"2001","unstructured":"Caudill, M. A. et al. Intracellular S-adenosylhomocysteine concentrations predict global DNA hypomethylation in tissues of methyl-deficient cystathionine beta-synthase heterozygous mice. J. Nutr 131, 2811\u20132818 (2001).","journal-title":"J. Nutr"},{"key":"3447_CR50","doi-asserted-by":"publisher","first-page":"14012","DOI":"10.1038\/s41598-018-32356-8","volume":"8","author":"L Beluzic","year":"2018","unstructured":"Beluzic, L. et al. Knock-down of AHCY and depletion of adenosine induces DNA damage and cell cycle arrest. Sci. Rep. 8, 14012 (2018).","journal-title":"Sci. Rep."},{"key":"3447_CR51","doi-asserted-by":"publisher","first-page":"1149","DOI":"10.3758\/BRM.41.4.1149","volume":"41","author":"E Erdfelder","year":"2009","unstructured":"Erdfelder, E., Faul, F., Buchner, A. & Lang, A. G. Statistical power analyses using G*Power 3.1: Tests for correlation and regression analyses. Behav. Res. Methods 41, 1149\u20131160 (2009).","journal-title":"Behav. Res. Methods"},{"key":"3447_CR52","doi-asserted-by":"crossref","unstructured":"Jernberg-Wiklund, H. and Nilsson, K. Multiple Myeloma Cell Lines. In: Masters JW and Palsson B, eds Human Cell Culture. New York: Kluwer Academic Publishers; 2002. p. 81\u2013155.","DOI":"10.1007\/0-306-46877-8_4"},{"key":"3447_CR53","doi-asserted-by":"crossref","first-page":"2762","DOI":"10.1002\/elps.201200605","volume":"34","author":"Z Le\u00f3n","year":"2013","unstructured":"Le\u00f3n, Z., Garc\u00eda-Ca\u00f1averas, J. C., Donato, M. T. & Lahoz, A. Mammalian cell metabolomics: experimental design and sample preparation. Electrophoresis 34, 2762\u20132775 (2013).","journal-title":"Electrophoresis"},{"key":"3447_CR54","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1007\/978-1-59745-244-1_13","volume":"358","author":"MR Viant","year":"2007","unstructured":"Viant, M. R. Revealing the metabolome of animal tissues using 1H nuclear magnetic resonance spectroscopy. Methods Mol. Biol 358, 229\u2013246 (2007).","journal-title":"Methods Mol. Biol"},{"key":"3447_CR55","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s11306-008-0137-z","volume":"5","author":"Q Teng","year":"2009","unstructured":"Teng, Q., Huang, W., Collette, T. W., Ekman, D. R. & Tan, C. A direct cell quenching method for cell-culture based metabolomics. Metabolomics 5, 199\u2013208 (2009).","journal-title":"Metabolomics"},{"key":"3447_CR56","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1007\/s11306-016-1058-x","volume":"12","author":"MKR Engskog","year":"2016","unstructured":"Engskog, M. K. R., Hagl\u00f6f, J., Arvidsson, T. & Pettersson, C. LC-MS based global metabolite profiling: the necessity of high data quality. Metabolomics 12, 114 (2016).","journal-title":"Metabolomics"},{"key":"3447_CR57","doi-asserted-by":"publisher","first-page":"779","DOI":"10.1021\/ac051437y","volume":"78","author":"CA Smith","year":"2006","unstructured":"Smith, C. A., Want, E. J., O'Maille, G., Abagyan, R. & Siuzdak, G. XCMS: processing mass spectrometry data for metabolite profiling using nonlinear peak alignment, matching, and identification. Anal. Chem. 78, 779\u2013787 (2006).","journal-title":"Anal. Chem."},{"key":"3447_CR58","doi-asserted-by":"publisher","first-page":"283","DOI":"10.1021\/ac202450g","volume":"84","author":"C Kuhl","year":"2012","unstructured":"Kuhl, C., Tautenhahn, R., B\u00f6ttcher, C., Larson, T. R. & Neumann, S. CAMERA: an integrated strategy for compound spectra extraction and annotation of liquid chromatography\/mass spectrometry data sets. Anal. Chem. 84, 283\u2013289 (2012).","journal-title":"Anal. Chem."},{"key":"3447_CR59","doi-asserted-by":"publisher","first-page":"4281","DOI":"10.1021\/ac051632c","volume":"78","author":"F Dieterle","year":"2006","unstructured":"Dieterle, F., Ross, A., Schlotterbeck, G. & Senn, H. Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in1H NMR metabonomics. Anal. Chem. 78, 4281\u20134290 (2006).","journal-title":"Anal. Chem."},{"key":"3447_CR60","doi-asserted-by":"publisher","first-page":"1005","DOI":"10.1038\/nprot.2010.50","volume":"5","author":"EJ Want","year":"2010","unstructured":"Want, E. J. et al. Global metabolic profiling procedures for urine using UPLC-MS. Nat Protoc. 5, 1005\u20131018 (2010).","journal-title":"Nat Protoc."},{"key":"3447_CR61","doi-asserted-by":"publisher","first-page":"1060","DOI":"10.1038\/nprot.2011.335","volume":"6","author":"WB Dunn","year":"2011","unstructured":"Dunn, W. B. et al. Procedures for large-scale metabolic profiling of serum and plasma using gas chromatography and liquid chromatography coupled to mass spectrometry. Nat. Protoc. 6, 1060\u20131083 (2011).","journal-title":"Nat. Protoc."},{"key":"3447_CR62","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1002\/cem.1006","volume":"20","author":"M Bylesj","year":"2006","unstructured":"Bylesj\u00f6, M. et al. OPLS discriminant analysis: combining the strengths of PLS-DA and SIMCA classification. J. Chemom 20, 341\u2013351 (2006).","journal-title":"J. Chemom"},{"key":"3447_CR63","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1021\/pr060594q","volume":"6","author":"J Trygg","year":"2007","unstructured":"Trygg, J., Holmes, E. & Lundstedt, T. Chemometrics in metabonomics. J. Proteome Res. 6, 469\u2013479 (2007).","journal-title":"J. Proteome Res."},{"key":"3447_CR64","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1007\/s11306-014-0656-8","volume":"10","author":"DJ Creek","year":"2014","unstructured":"Creek, D. J. et al. Metabolite identification: are you sure? And how do your peers gauge your confidence?. Metabolomics 10, 350\u2013353 (2014).","journal-title":"Metabolomics"},{"key":"3447_CR65","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1038\/nmeth.2089","volume":"9","author":"CA Schneider","year":"2012","unstructured":"Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671\u2013675 (2012).","journal-title":"Nat. Methods"},{"key":"3447_CR66","doi-asserted-by":"publisher","first-page":"1047","DOI":"10.1177\/1087057114532352","volume":"19","author":"A Walzl","year":"2014","unstructured":"Walzl, A. et al. The resazurin reduction assay can distinguish cytotoxic from cytostatic compounds in spheroid screening assays. J. Biomol. Screen 19, 1047\u20131059 (2014).","journal-title":"J. Biomol. Screen"},{"key":"3447_CR67","doi-asserted-by":"publisher","first-page":"2827","DOI":"10.1182\/blood-2009-03-211045","volume":"115","author":"JJ Driscoll","year":"2010","unstructured":"Driscoll, J. J. et al. The sumoylation pathway is dysregulated in multiple myeloma and is associated with adverse patient outcome. Blood 115, 2827\u20132834 (2010).","journal-title":"Blood"},{"key":"3447_CR68","doi-asserted-by":"publisher","first-page":"549","DOI":"10.1038\/ng1547","volume":"37","author":"KL Gunderson","year":"2005","unstructured":"Gunderson, K. L., Steemers, F. J., Lee, G., Mendoza, L. G. & Chee, M. S. A genome-wide scalable SNP genotyping assay using microarray technology. Nat. Genet. 37, 549\u2013554 (2005).","journal-title":"Nat. Genet."},{"key":"3447_CR69","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nmeth842","volume":"3","author":"FJ Steemers","year":"2006","unstructured":"Steemers, F. J. et al. Whole-genome genotyping with the single-base extension assay. Nat. Methods 3, 31\u201333 (2006).","journal-title":"Nat. Methods"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03447-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03447-8","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03447-8.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,20]],"date-time":"2023-10-20T23:07:58Z","timestamp":1697843278000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03447-8"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,12]]},"references-count":69,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["3447"],"URL":"https:\/\/doi.org\/10.1038\/s41419-021-03447-8","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,2,12]]},"assertion":[{"value":"9 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 January 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 January 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Mice were housed and treated following conditions approved by the Ethical Committee for Animal Experiments, VUB (CEP 17-281-3).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical statement"}},{"value":"The authors declare that they have no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"167"}}