{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T09:59:55Z","timestamp":1790589595871,"version":"4.1.0"},"reference-count":42,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T00:00:00Z","timestamp":1790553600000},"content-version":"vor","delay-in-days":270,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,1,1]],"date-time":"2026-01-01T00:00:00Z","timestamp":1767225600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Analytical Cellular Pathology"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Background and Purpose<\/jats:title>\n                    <jats:p>The malignant progression of nonsmall cell lung cancer (NSCLC) is closely related to cancer stemness. Histone deacetylase 4 (HDAC4) plays a regulatory role in lung cancer, but its effect on NSCLC stemness remains unclear. This study aimed to investigate the role and mechanism of HDAC4 in NSCLC stemness.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, a tumor\u2010bearing model was established by subcutaneously injecting A549 cells into the right dorsal side of nude mice. Reverse transcription quantitative polymerase chain reaction (RT\u2010qPCR), Western blotting, and immunohistochemistry were used to measure gene and protein expression levels. Flow cytometry, sphere formation assays, and Transwell experiments were employed to assess cancer cell stemness, migration, and invasion. Additionally, a kit was used to measure changes in glutamine metabolism\u2010related indicators.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, we found that knocking down HDAC4 expression inhibited the expression of SRY\u2010box transcription factor 2 (SOX2), octamer\u2010binding transcription factor 4 (OCT4), and nanog homeobox (NANOG) in A549 cells; it also reduced the proportions of CD133\u2010 and CD44\u2010positive cells and suppressed their sphere formation, cell migration, and invasion abilities. Furthermore, HDAC4 knockdown inhibited glutamine uptake, glutamate production, \u03b1\u2010ketoglutarate levels, and glutaminase (GLS) activity. Notably, treatment with the additional glutamine metabolism inhibitor CB\u2010839 attenuated the promoting effects of HDAC4 overexpression on the stemness, migration, and invasion of A549 cells. In addition, HDAC4 promoted the expression of hypoxia\u2010inducible factor\u20101 alpha (HIF\u20101\u03b1) and solute carrier family 38 member 2 (SLC38A2); after overexpressing HIF\u20101\u03b1, the inhibitory effect of HDAC4 knockdown on SLC38A2 expression in A549 cells was weakened.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study reveals a critical mechanism by which HDAC4 enhances glutamine metabolism through upregulation of HIF\u20101\u03b1 expression to promote SLC38A2 expression, thereby driving NSCLC stemness and progression.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1155\/ancp\/2525721","type":"journal-article","created":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T09:48:40Z","timestamp":1790588920000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HDAC4 Promotes Cancer Stemness in Nonsmall Cell Lung Cancer by Upregulating SLC38A2 Expression via HIF\u20101\u03b1 to Enhance Glutamine Metabolism"],"prefix":"10.1155","volume":"2026","author":[{"given":"Changxian","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoming","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenwu","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxue","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liju","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingyu","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7528-3832","authenticated-orcid":false,"given":"Weimin","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6381-8369","authenticated-orcid":false,"given":"Weijun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,28]]},"reference":[{"key":"e_1_2_12_1_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1369356"},{"key":"e_1_2_12_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2022.06.010"},{"key":"e_1_2_12_3_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-010-9216-5"},{"key":"e_1_2_12_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2013.04.017"},{"key":"e_1_2_12_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1459978"},{"key":"e_1_2_12_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-00971-9"},{"key":"e_1_2_12_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0709747104"},{"key":"e_1_2_12_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2015.381"},{"key":"e_1_2_12_9_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.167874"},{"key":"e_1_2_12_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-021-01636-y"},{"key":"e_1_2_12_11_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.58655"},{"key":"e_1_2_12_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuropharm.2019.107789"},{"key":"e_1_2_12_13_2","doi-asserted-by":"crossref","DOI":"10.1016\/j.canlet.2025.218219","article-title":"HHLA2 Promotes Immune Evasion in EGFR-Mutant Lung Cancer by Inhibiting CD8(+) T Cell Glutamine Metabolism via KIR3DL3 Interaction","volume":"639","author":"Wu F.","year":"2025","journal-title":"Cancer Letters"},{"key":"e_1_2_12_14_2","doi-asserted-by":"publisher","DOI":"10.3389\/fncel.2015.00042"},{"key":"e_1_2_12_15_2","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2018.4564"},{"key":"e_1_2_12_16_2","doi-asserted-by":"publisher","DOI":"10.18632\/aging.100980"},{"key":"e_1_2_12_17_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0098894"},{"key":"e_1_2_12_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.15410"},{"key":"e_1_2_12_19_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.29673"},{"key":"e_1_2_12_20_2","doi-asserted-by":"publisher","DOI":"10.2174\/1568009623666230329123358"},{"key":"e_1_2_12_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s40170-026-00433-6"},{"key":"e_1_2_12_22_2","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2023.13676"},{"key":"e_1_2_12_23_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tox.2025.154390"},{"key":"e_1_2_12_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.257055"},{"key":"e_1_2_12_25_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1818521116"},{"key":"e_1_2_12_26_2","doi-asserted-by":"publisher","DOI":"10.21037\/jtd-20-1555"},{"key":"e_1_2_12_27_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24032337"},{"key":"e_1_2_12_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2023.216171"},{"key":"e_1_2_12_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/onc.2017.51"},{"key":"e_1_2_12_30_2","doi-asserted-by":"publisher","DOI":"10.1177\/1758835919855228"},{"key":"e_1_2_12_31_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcb.29365"},{"key":"e_1_2_12_32_2","doi-asserted-by":"publisher","DOI":"10.1111\/1759-7714.12825"},{"key":"e_1_2_12_33_2","doi-asserted-by":"publisher","DOI":"10.21037\/tlcr-21-982"},{"key":"e_1_2_12_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.trecan.2017.01.005"},{"key":"e_1_2_12_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-018-0074-8"},{"key":"e_1_2_12_36_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-23-3748"},{"key":"e_1_2_12_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tranon.2020.100920"},{"key":"e_1_2_12_38_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12957-022-02777-x"},{"key":"e_1_2_12_39_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.5150"},{"key":"e_1_2_12_40_2","doi-asserted-by":"publisher","DOI":"10.7150\/thno.43839"},{"key":"e_1_2_12_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2019.07.039"},{"key":"e_1_2_12_42_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-020-01729-3"}],"container-title":["Analytical Cellular Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/ancp\/2525721","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1155\/ancp\/2525721","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1155\/ancp\/2525721","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T09:48:41Z","timestamp":1790588921000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1155\/ancp\/2525721"}},"subtitle":[],"editor":[{"given":"Shih-Min","family":"Hsia","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,1]]},"references-count":42,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1155\/ancp\/2525721"],"URL":"https:\/\/doi.org\/10.1155\/ancp\/2525721","archive":["Portico"],"relation":{},"ISSN":["2210-7177","2210-7185"],"issn-type":[{"value":"2210-7177","type":"print"},{"value":"2210-7185","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1]]},"assertion":[{"value":"2026-02-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-09","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2525721"}}