{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T12:53:59Z","timestamp":1792673639195,"version":"4.5.0"},"reference-count":26,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T00:00:00Z","timestamp":1565568000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T00:00:00Z","timestamp":1565568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000057","name":"U.S. Department of Health &amp; Human Services | NIH | National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["R01GM131044"],"award-info":[{"award-number":["R01GM131044"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Heterochromatin is a tightly packed form of DNA involved in gene silencing, chromosome segregation, and protection of genome stability. Heterochromatin is becoming more recognized in tumor suppression and may thus serve as a potential target for cancer therapy. However, to date there are no drugs that are well established to specifically promote heterochromatin formation. Here, we describe a screening method using <jats:italic>Drosophila<\/jats:italic> to identify small molecule compounds that promote heterochromatin formation, with the purpose of developing epigenetic cancer therapeutics. We took advantage of a <jats:italic>Drosophila<\/jats:italic> strain with a variegated eye color phenotype that is sensitive to heterochromatin levels, and screened a library of 97 FDA approved oncology drugs. This screen identified methotrexate as the most potent small molecule drug, among the 97 oncology drugs screened, in promoting heterochromatin formation. Interestingly, methotrexate has been identified as a JAK\/STAT inhibitor in a functional screen, causing reduced phosphorylation of STAT proteins. These findings are in line with our previous observation that unphosphorylated STAT (uSTAT) promotes heterochromatin formation in both <jats:italic>Drosophila<\/jats:italic> and human cells and suppresses tumor growth in mouse xenografts. Thus, <jats:italic>Drosophila<\/jats:italic> with variegated eye color phenotypes could be an effective tool for screening heterochromatin-promoting compounds that could be candidates as cancer therapeutics.<\/jats:p>","DOI":"10.1038\/s41598-019-48137-w","type":"journal-article","created":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T10:03:15Z","timestamp":1565604195000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Identification of methotrexate as a heterochromatin-promoting drug"],"prefix":"10.1038","volume":"9","author":[{"given":"Andre C.","family":"Loyola","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin","family":"Shang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pranabananda","family":"Dutta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinghong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9041-7341","authenticated-orcid":false,"given":"Willis X.","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,8,12]]},"reference":[{"key":"48137_CR1","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1038\/nrm.2017.119","volume":"19","author":"RC Allshire","year":"2018","unstructured":"Allshire, R. C. & Madhani, H. D. Ten principles of heterochromatin formation and function. Nat Rev Mol Cell Biol 19, 229\u2013244, https:\/\/doi.org\/10.1038\/nrm.2017.119 (2018).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"48137_CR2","doi-asserted-by":"publisher","first-page":"265","DOI":"10.1146\/annurev-cellbio-100617-062653","volume":"34","author":"A Janssen","year":"2018","unstructured":"Janssen, A., Colmenares, S. U. & Karpen, G. H. Heterochromatin: Guardian of the Genome. Annu Rev Cell Dev Biol 34, 265\u2013288, https:\/\/doi.org\/10.1146\/annurev-cellbio-100617-062653 (2018).","journal-title":"Annu Rev Cell Dev Biol"},{"key":"48137_CR3","doi-asserted-by":"publisher","first-page":"1119","DOI":"10.1242\/jcs.026104","volume":"121","author":"A Rego","year":"2008","unstructured":"Rego, A., Sinclair, P. B., Tao, W., Kireev, I. & Belmont, A. S. The facultative heterochromatin of the inactive X chromosome has a distinctive condensed ultrastructure. J Cell Sci 121, 1119\u20131127, https:\/\/doi.org\/10.1242\/jcs.026104 (2008).","journal-title":"J Cell Sci"},{"key":"48137_CR4","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1126\/science.1063127","volume":"293","author":"T Jenuwein","year":"2001","unstructured":"Jenuwein, T. & Allis, C. D. Translating the histone code. Science 293, 1074\u20131080, https:\/\/doi.org\/10.1126\/science.1063127 (2001).","journal-title":"Science"},{"key":"48137_CR5","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.mrfmmm.2008.09.007","volume":"647","author":"GK Dialynas","year":"2008","unstructured":"Dialynas, G. K., Vitalini, M. W. & Wallrath, L. L. Linking Heterochromatin Protein 1 (HP1) to cancer progression. Mutation research 647, 13\u201320, https:\/\/doi.org\/10.1016\/j.mrfmmm.2008.09.007 (2008).","journal-title":"Mutation research"},{"key":"48137_CR6","doi-asserted-by":"publisher","first-page":"18668","DOI":"10.1074\/jbc.M512454200","volume":"281","author":"LE Norwood","year":"2006","unstructured":"Norwood, L. E. et al. A requirement for dimerization of HP1Hsalpha in suppression of breast cancer invasion. The Journal of biological chemistry 281, 18668\u201318676 (2006).","journal-title":"The Journal of biological chemistry"},{"key":"48137_CR7","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/nature10371","volume":"477","author":"Q Zhu","year":"2011","unstructured":"Zhu, Q. et al. BRCA1 tumour suppression occurs via heterochromatin-mediated silencing. Nature 477, 179\u2013184, https:\/\/doi.org\/10.1038\/nature10371 (2011).","journal-title":"Nature"},{"key":"48137_CR8","doi-asserted-by":"publisher","first-page":"641","DOI":"10.4161\/cc.27527","volume":"13","author":"S Talluri","year":"2014","unstructured":"Talluri, S. & Dick, F. A. The retinoblastoma protein and PML collaborate to organize heterochromatin and silence E2F-responsive genes during senescence. Cell Cycle 13, 641\u2013651, https:\/\/doi.org\/10.4161\/cc.27527 (2014).","journal-title":"Cell Cycle"},{"key":"48137_CR9","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1038\/ncb1235","volume":"7","author":"S Gonzalo","year":"2005","unstructured":"Gonzalo, S. et al. Role of the RB1 family in stabilizing histone methylation at constitutive heterochromatin. 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CSH Protoc 2008, pdb prot4708, https:\/\/doi.org\/10.1101\/pdb.prot4708 (2008).","journal-title":"CSH Protoc"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-48137-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-48137-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-48137-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T12:32:40Z","timestamp":1671280360000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-48137-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,12]]},"references-count":26,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["48137"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-48137-w","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,8,12]]},"assertion":[{"value":"7 March 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 July 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"11673"}}