{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T18:01:24Z","timestamp":1786557684367,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 114-2314-B-038-137"],"award-info":[{"award-number":["NSTC 114-2314-B-038-137"]}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"crossref","award":["112TMU-SHH-15"],"award-info":[{"award-number":["112TMU-SHH-15"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"crossref","award":["113TMU-SHH-10"],"award-info":[{"award-number":["113TMU-SHH-10"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"crossref","award":["114TMU-SHH-15"],"award-info":[{"award-number":["114TMU-SHH-15"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Colorectal cancer (CRC) progression and therapy resistance are driven in part by metabolic reprogramming and the persistence of cancer stem-like cells (CSCs). The seven in absentia homolog 2 (SIAH2)\/with-no-lysine kinase 1 (WNK1) signaling axis has emerged as a potential regulator of these processes, yet its functional role in CRC metabolism and tumor\u2013stroma crosstalk remains incompletely understood. Integrated analyses of The Cancer Genome Atlas\u2013Colon Adenocarcinoma (TCGA-COAD) and Gene Expression Omnibus (GEO, GSE17538) datasets revealed significant upregulation of SIAH2 and WNK1 in CRC tissues, with strong positive correlations to glycolysis- and hypoxia-associated genes, including PFKP, LDHA, BPGM, ADH1A, ADH1B, and HIF-1\u03b1. Single-cell and clinical profiling further demonstrated preferential enrichment of SIAH2 in undifferentiated, stem-like tumor cell populations. Functional studies across multiple CRC cell lines showed that SIAH2 silencing suppressed proliferation, clonogenic growth, tumor sphere formation, and cell-cycle progression, whereas SIAH2 overexpression exerted opposite effects. Seahorse extracellular flux analyses established that SIAH2 promotes glycolytic capacity and metabolic flexibility. At the protein level, SIAH2 regulated glycolytic enzymes and WNK1\/hypoxia-inducible factor-1\u03b1 (HIF-1\u03b1) signaling, effects that were amplified by cancer-associated fibroblast (CAF)-derived conditioned medium. CAF exposure enhanced SIAH2 expression, CSC spheroid growth, and resistance to fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy, whereas SIAH2 depletion effectively abrogated these effects. Collectively, these findings identify the SIAH2\/WNK1 axis as a central metabolic regulator linking glycolysis, CSC maintenance, and microenvironment-driven therapy resistance in CRC, highlighting its potential as a therapeutic target.<\/jats:p>","DOI":"10.3390\/ijms27021065","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T13:59:54Z","timestamp":1769003994000},"page":"1065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["SIAH2\u2013WNK1 Signaling Drives Glycolytic Metabolism and Therapeutic Resistance in Colorectal Cancer"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9703-7480","authenticated-orcid":false,"given":"Kee-Thai","family":"Kiu","sequence":"first","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 235, Taiwan"},{"name":"Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1002-8640","authenticated-orcid":false,"given":"Cheng-Ying","family":"Chu","sequence":"additional","affiliation":[{"name":"CRISPR Gene Targeting Core, Taipei Medical University, Taipei 110, Taiwan"},{"name":"TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8317-1339","authenticated-orcid":false,"given":"Yi-Chiao","family":"Cheng","sequence":"additional","affiliation":[{"name":"Division of Colon and Rectal Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei 114, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Hsuan","family":"Yen","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 235, Taiwan"},{"name":"Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying-Wei","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 235, Taiwan"},{"name":"Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2149-325X","authenticated-orcid":false,"given":"Narpati Wesa","family":"Pikatan","sequence":"additional","affiliation":[{"name":"Division of Urology, Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2679-1205","authenticated-orcid":false,"given":"Vijesh Kumar","family":"Yadav","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 235, Taiwan"},{"name":"Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2185-0832","authenticated-orcid":false,"given":"Tung-Cheng","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Colorectal Surgery, Department of Surgery, Taipei Medical University Shuang-Ho Hospital, New Taipei City 235, Taiwan"},{"name":"Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1016\/j.jfma.2019.08.023","article-title":"Cancers in Taiwan: Practical insight from epidemiology, treatments, biomarkers, and cost","volume":"119","author":"Kuo","year":"2020","journal-title":"J. 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