{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T21:40:22Z","timestamp":1789508422804,"version":"build-2803163510"},"reference-count":61,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,31]],"date-time":"2023-12-31T00:00:00Z","timestamp":1703980800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science Centre grant Miniatura","award":["2021\/05\/X\/NZ5\/00614"],"award-info":[{"award-number":["2021\/05\/X\/NZ5\/00614"]}]},{"name":"National Science Centre grant Miniatura","award":["002\/RID\/2018\/19"],"award-info":[{"award-number":["002\/RID\/2018\/19"]}]},{"name":"Minister of Science and Higher Education","award":["2021\/05\/X\/NZ5\/00614"],"award-info":[{"award-number":["2021\/05\/X\/NZ5\/00614"]}]},{"name":"Minister of Science and Higher Education","award":["002\/RID\/2018\/19"],"award-info":[{"award-number":["002\/RID\/2018\/19"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Multiple myeloma (MM) is a plasma cell malignancy that, despite recent advances in therapy, continues to pose a major challenge to hematologists. Currently, different classes of drugs are applied to treat MM, among others, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies. Most of them participate in an interplay with the immune system, hijacking its effector functions and redirecting them to anti-MM activity. Therefore, adjuvant therapies boosting the immune system may be potentially beneficial in MM therapy. Vitamin D (VD) and vitamin K (VK) have multiple so called \u201cnon-classical\u201d actions. They exhibit various anti-inflammatory and anti-cancer properties. In this paper, we investigated the influence of VD and VK on epigenetic alterations associated with the proliferative potential of MM cells and the development of BTZ resistance. Our results showed that the development of BTZ resistance is associated with a global decrease in DNA methylation. On the contrary, both control MM cells and BTZ-resistant MM cells exposed to VD alone and to the combination of VD and VK exhibit a global increase in methylation. In conclusion, VD and VK in vitro have the potential to induce epigenetic changes that reduce the proliferative potential of plasma cells and may at least partially prevent the development of resistance to BTZ. However, further ex vivo and in vivo studies are needed to confirm the results and introduce new supplementation recommendations as part of adjuvant therapy.<\/jats:p>","DOI":"10.3390\/nu16010142","type":"journal-article","created":{"date-parts":[[2023,12,31]],"date-time":"2023-12-31T04:51:51Z","timestamp":1703998311000},"page":"142","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Vitamin D and K Supplementation Is Associated with Changes in the Methylation Profile of U266-Multiple Myeloma Cells, Influencing the Proliferative Potential and Resistance to Bortezomib"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4008-7473","authenticated-orcid":false,"given":"Karolina","family":"\u0141uczkowska","sequence":"first","affiliation":[{"name":"Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8695-8863","authenticated-orcid":false,"given":"Piotr","family":"Kulig","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-5844","authenticated-orcid":false,"given":"Bart\u0142omiej","family":"Baumert","sequence":"additional","affiliation":[{"name":"Department of Hematology and Transplantology, Pomeranian Medical University, 71-252 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bogus\u0142aw","family":"Machali\u0144ski","sequence":"additional","affiliation":[{"name":"Department of General Pathology, Pomeranian Medical University, 70-111 Szczecin, Poland"},{"name":"Department of Hematology and Transplantology, Pomeranian Medical University, 71-252 Szczecin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1146\/annurev.med.57.042905.122625","article-title":"Bortezomib: Proteasome Inhibition as an Effective Anticancer Therapy","volume":"57","author":"Richardson","year":"2006","journal-title":"Annu. Rev. Med."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"\u0141uczkowska, K., Rogi\u0144ska, D., Kulig, P., Bielikowicz, A., Baumert, B., and Machali\u0144ski, B. (2022). Bortezomib-Induced Epigenetic Alterations in Nerve Cells: Focus on the Mechanisms Contributing to the Peripheral Neuropathy Development. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052431"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"\u0141uczkowska, K., Rogi\u0144ska, D., Ula\u0144czyk, Z., Paczkowska, E., Schmidt, C.A., and Machali\u0144ski, B. (2020). Molecular Mechanisms of Bortezomib Action: Novel Evidence for the miRNA\u2013mRNA Interaction Involvement. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21010350"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"9846","DOI":"10.1038\/s41598-021-89128-0","article-title":"Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound","volume":"11","author":"Sokolowska","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_5","first-page":"1","article-title":"Exploring vitamin D metabolism and function in cancer","volume":"50","author":"Jeon","year":"2018","journal-title":"Exp. Mol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1152\/physrev.00014.2015","article-title":"Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects","volume":"96","author":"Christakos","year":"2016","journal-title":"Physiol. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Hii, C.S., and Ferrante, A. (2016). The Non-Genomic Actions of Vitamin D. Nutrients, 8.","DOI":"10.3390\/nu8030135"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"12670","DOI":"10.1038\/s41598-022-15924-x","article-title":"Characterization of methylation patterns associated with lifestyle factors and vitamin D supplementation in a healthy elderly cohort from Southwest Sweden","volume":"12","author":"Cruz","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jsbmb.2014.01.018","article-title":"In vitro exposure of human blood mononuclear cells to active vitamin D does not induce substantial change to DNA methylation on a genome-scale","volume":"141","author":"Valencia","year":"2014","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1038\/s41590-021-01080-3","article-title":"Autocrine vitamin D signaling switches off pro-inflammatory programs of TH1 cells","volume":"23","author":"Chauss","year":"2021","journal-title":"Nat. Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"\u0141uczkowska, K., Kulig, P., Baumert, B., and Machali\u0144ski, B. (2022). The Evidence That 25(OH)D3 and VK2 MK-7 Vitamins Influence the Proliferative Potential and Gene Expression Profiles of Multiple Myeloma Cells and the Development of Resistance to Bortezomib. Nutrients, 14.","DOI":"10.3390\/nu14235190"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1006\/abbi.1999.1605","article-title":"Expression of 1,25-Dihydroxyvitamin D3 Receptor in the Immune System","volume":"374","author":"Veldman","year":"2000","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2449","DOI":"10.1002\/cam4.2119","article-title":"Vitamin D _3 enhances the response to cisplatin in bladder cancer through VDR and TA p73 signaling crosstalk","volume":"8","author":"Bunch","year":"2019","journal-title":"Cancer Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1159\/000080693","article-title":"Effects of Dexamethasone, All-Trans Retinoic Acid, Vitamin D_3 and Interferon-\u03b1 on FO Myeloma Cells","volume":"50","author":"Ozdemir","year":"2004","journal-title":"Chemotherapy"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2445","DOI":"10.1038\/s41375-018-0114-0","article-title":"Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway","volume":"32","author":"Busch","year":"2018","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Kulig, P., \u0141uczkowska, K., Bielikowicz, A., Zdrojewska, D., Baumert, B., and Machali\u0144ski, B. (2022). Vitamin D as a Potential Player in Immunologic Control over Multiple Myeloma Cells: Implications for Adjuvant Therapies. Nutrients, 14.","DOI":"10.3390\/nu14091802"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7714","DOI":"10.1038\/s41598-020-64880-x","article-title":"Vitamin K2 promotes PI3K\/AKT\/HIF-1\u03b1-mediated glycolysis that leads to AMPK-dependent autophagic cell death in bladder cancer cells","volume":"10","author":"Duan","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1111\/cbdd.13696","article-title":"Cytotoxic effects of vitamins K1, K2, and K3 against human T lymphoblastoid leukemia cells through apoptosis induction and cell cycle arrest","volume":"96","author":"Xu","year":"2020","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"629","DOI":"10.4161\/auto.5941","article-title":"Vitamin K2 induces autophagy and apoptosis simultaneously in leukemia cells","volume":"4","author":"Yokoyama","year":"2008","journal-title":"Autophagy"},{"key":"ref_20","first-page":"613","article-title":"The mechanisms of vitamin K2-induced apoptosis of myeloma cells","volume":"91","author":"Tsujioka","year":"2006","journal-title":"Haematologica"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1007\/s002239900700","article-title":"The effect of vitamin K and D supplementation on ovariectomy-induced bone loss","volume":"65","author":"Matsunaga","year":"1999","journal-title":"Calcif. Tissue Int."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/S0378-5122(01)00275-4","article-title":"Effect of continuous combined therapy with vitamin K2 and vitamin D3 on bone mineral density and coagulofibrinolysis function in postmenopausal women","volume":"41","author":"Ushiroyama","year":"2002","journal-title":"Maturitas"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1160\/TH03-07-0423","article-title":"Beneficial effects of vitamins D and K on the elastic properties of the vessel wall in postmenopausal women: A follow-up study","volume":"91","author":"Braam","year":"2004","journal-title":"Thromb Haemost."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"631","DOI":"10.20452\/pamw.3041","article-title":"Effect of vitamin K2 on progression of atherosclerosis and vascular calcification in nondialyzed patients with chronic kidney disease stages 3\u20135","volume":"125","author":"Kurnatowska","year":"2015","journal-title":"Pol. Arch. Intern. Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Luczkowska, K., Kulig, P., Rusi\u0144ska, K., Baumert, B., and Machali\u0144ski, B. (2023). 5-Aza-2\u2032-Deoxycytidine Alters the Methylation Profile of Bortezomib-Resistant U266 Multiple Myeloma Cells and Affects Their Proliferative Potential. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms242316780"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1038\/s41418-021-00739-6","article-title":"FBXL6 degrades phosphorylated p53 to promote tumor growth","volume":"28","author":"Li","year":"2021","journal-title":"Cell Death Differ."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Sugiaman-Trapman, D., Vitezic, M., Jouhilahti, E.-M., Mathelier, A., Lauter, G., Misra, S., Daub, C.O., Kere, J., and Swoboda, P. (2018). Characterization of the human RFX transcription factor family by regulatory and target gene analysis. BMC Genom., 19.","DOI":"10.1186\/s12864-018-4564-6"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1016\/j.bbrc.2022.04.069","article-title":"Inactivation of axon guidance molecule netrin-1 in human colorectal cancer by an epigenetic mechanism","volume":"611","author":"Nakayama","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s11010-021-04274-3","article-title":"The role of GTPase-activating protein ARHGAP26 in human cancers","volume":"477","author":"Zhang","year":"2021","journal-title":"Mol. Cell. Biochem."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Kulig, P., Milczarek, S., Bakinowska, E., Szalewska, L., Baumert, B., and Machali\u0144ski, B. (2023). Lenalidomide in Multiple Myeloma: Review of Resistance Mechanisms, Current Treatment Strategies and Future Perspectives. Cancers, 15.","DOI":"10.3390\/cancers15030963"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"S13","DOI":"10.1016\/S0268-960X(10)70004-7","article-title":"Lenalidomide mode of action: Linking bench and clinical findings","volume":"24","author":"Davies","year":"2010","journal-title":"Blood Rev."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/s41408-021-00478-4","article-title":"A phase 2 study of isatuximab monotherapy in patients with multiple myeloma who are refractory to daratumumab","volume":"11","author":"Mikhael","year":"2021","journal-title":"Blood Cancer J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7891","DOI":"10.2147\/CMAR.S212526","article-title":"Evaluating Daratumumab in the Treatment of Multiple Myeloma: Safety, Efficacy and Place in Therapy","volume":"12","author":"Dima","year":"2020","journal-title":"Cancer Manag. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2962","DOI":"10.1182\/blood.V120.21.2962.2962","article-title":"A Phase 2 Study of Prolonged Carfilzomib Therapy in Patients with Multiple Myeloma Previously Enrolled in Carfilzomib Clinical Trials","volume":"120","author":"Siegel","year":"2012","journal-title":"Blood"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1056\/NEJMoa1606038","article-title":"Daratumumab, Bortezomib, and Dexamethasone for Multiple Myeloma","volume":"375","author":"Palumbo","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/S0140-6736(19)31240-1","article-title":"Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study","volume":"394","author":"Moreau","year":"2019","journal-title":"Lancet"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1182\/blood.2020005288","article-title":"Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial","volume":"136","author":"Voorhees","year":"2020","journal-title":"Blood"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2104","DOI":"10.1056\/NEJMoa1817249","article-title":"Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma","volume":"380","author":"Facon","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.coph.2010.04.001","article-title":"Vitamin D: Modulator of the immune system","volume":"10","author":"Baeke","year":"2010","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.ecl.2017.07.007","article-title":"Vitamin D Receptor Signaling and Cancer","volume":"46","author":"Campbell","year":"2017","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0304-3835(97)00298-X","article-title":"Effects of vitamin D3 on proliferation of cancer cells in vitro","volume":"120","author":"Fife","year":"1997","journal-title":"Cancer Lett."},{"key":"ref_42","first-page":"533","article-title":"The induction of apoptosis by a combined 1,25(OH)2D3 analog, EB1089 and TGF-\u03b21 in NCI-H929 multiple myeloma cells","volume":"20","author":"Park","year":"2002","journal-title":"Int. J. Oncol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1006\/excr.1999.4735","article-title":"Cell Cycle Arrest Induced by the Vitamin D3 Analog EB1089 in NCI-H929 Myeloma Cells Is Associated with Induction of the Cyclin-Dependent Kinase Inhibitor p27","volume":"254","author":"Park","year":"2000","journal-title":"Exp. Cell Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1046\/j.1365-2141.2000.02046.x","article-title":"Induction of apoptosis by vitamin D _3 analogue EB1089 in NCI-H929 myeloma cells via activation of caspase 3 and p38 MAP kinase: Induction of Apoptosis by EB1089 in NCI-H929 Cells","volume":"109","author":"Park","year":"2000","journal-title":"Br. J. Haematol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s00520-021-06414-3","article-title":"High prevalence of peripheral neuropathy in multiple myeloma patients and the impact of vitamin D levels, a cross-sectional study","volume":"30","author":"Oortgiesen","year":"2021","journal-title":"Support. Care Cancer"},{"key":"ref_46","first-page":"3105","article-title":"Low serum vitamin D occurs commonly among multiple myeloma patients treated with bortezomib and\/or thalidomide and is associated with severe neuropathy","volume":"24","author":"Wang","year":"2016","journal-title":"Support. Care Cancer"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1002\/hon.2774","article-title":"Reduced survival after autologous stem cell transplantation in myeloma and lymphoma patients with low vitamin D serum levels","volume":"38","author":"Eicher","year":"2020","journal-title":"Hematol. Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1002\/hon.2827","article-title":"Gene expression profile unveils diverse biological effect of serum vitamin D in Hodgkin\u2019s and diffuse large B-cell lymphoma","volume":"39","author":"Donati","year":"2020","journal-title":"Hematol. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1111\/pcmr.12760","article-title":"The myelin protein PMP2 is regulated by SOX10 and drives melanoma cell invasion","volume":"32","author":"Graf","year":"2019","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8954","DOI":"10.1158\/0008-5472.CAN-07-6088","article-title":"DNA Hypomethylation Arises Later in Prostate Cancer Progression than CpG Island Hypermethylation and Contributes to Metastatic Tumor Heterogeneity","volume":"68","author":"Yegnasubramanian","year":"2008","journal-title":"Cancer Res"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/pcan.2014.45","article-title":"Global DNA hypomethylation in prostate cancer development and progression: A systematic review","volume":"18","author":"Zelic","year":"2014","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1111\/bjh.13506","article-title":"Global hypomethylation in myeloma is associated with poor prognosis","volume":"172","author":"Sive","year":"2015","journal-title":"Br. J. Haematol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2966","DOI":"10.4049\/jimmunol.1202493","article-title":"Myeloma Is Characterized by Stage-Specific Alterations in DNA Methylation That Occur Early during Myelomagenesis","volume":"190","author":"Heuck","year":"2013","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s12964-022-00935-y","article-title":"Netrin-1 induces the anti-apoptotic and pro-survival effects of B-ALL cells through the Unc5b-MAPK axis","volume":"20","author":"Huang","year":"2022","journal-title":"Cell Commun. Signal."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"11142","DOI":"10.1111\/jcmm.17036","article-title":"Down-regulation of MYH10 driven by chromosome 17p13.1 deletion promotes hepatocellular carcinoma metastasis through activation of the EGFR pathway","volume":"25","author":"Jin","year":"2021","journal-title":"J. Cell. Mol. Med."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.leukres.2010.10.013","article-title":"Abnormal methylation of GRAF promoter Chinese patients with acute myeloid leukemia","volume":"35","author":"Qian","year":"2011","journal-title":"Leuk. Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/sj.bjc.6602939","article-title":"Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome","volume":"94","author":"Bojesen","year":"2006","journal-title":"Br. J. Cancer"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"5281","DOI":"10.7314\/APJCP.2013.14.9.5281","article-title":"Identifying Differentially Expressed Genes and Small Molecule Drugs for Prostate Cancer by a Bioinformatics Strategy","volume":"14","author":"Li","year":"2013","journal-title":"Asian Pac. J. Cancer Prev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1186\/s13148-021-01135-0","article-title":"Evaluation of global and intragenic hypomethylation in colorectal adenomas improves patient stratification and colorectal cancer risk prediction","volume":"13","author":"Debernardi","year":"2021","journal-title":"Clin. Epigenetics"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s40246-016-0071-5","article-title":"Hypomethylation coordinates antagonistically with hypermethylation in cancer development: A case study of leukemia","volume":"10","author":"Kushwaha","year":"2016","journal-title":"Hum. Genom."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"534","DOI":"10.1158\/1940-6207.CAPR-15-0349","article-title":"DNA Hypomethylation Contributes to Genomic Instability and Intestinal Cancer Initiation","volume":"9","author":"Sheaffer","year":"2016","journal-title":"Cancer Prev. Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/1\/142\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:45:17Z","timestamp":1760132717000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/16\/1\/142"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,31]]},"references-count":61,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["nu16010142"],"URL":"https:\/\/doi.org\/10.3390\/nu16010142","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,31]]}}}