{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:56:34Z","timestamp":1781862994772,"version":"3.54.5"},"reference-count":51,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01-CA269580"],"award-info":[{"award-number":["R01-CA269580"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Syd Kyle Endowment"},{"name":"Texas A&M AgriLife"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: The orphan nuclear receptors 4A1 (NR4A1) and NR4A2 are overexpressed in multiple solid tumors, and both receptors exhibit tumor promoter-like activities. A recent study reported that luteolin, a flavonoid that binds NR4A1, decreased the expression of the pro-oncogenic receptor tyrosine kinase MerTK in colon cancer cells. Methods\/Results: In this study, we observed that MerTK protein was expressed in human SW480 and HCT116 and mouse CT26 colon cancer cell lines, and was significantly downregulated after treatment with 1,1-bis(3\u2032-indolyl)-1-(3,5-disubstitutedphenyl)methane (DIM-3,5) compounds, which are dual NR4A1\/NR4A2 ligands. Moreover, knockdown of NR4A1 and NR4A2 also decreased MerTK protein expression and DIM-3,5 ligands, and receptor knockdown also decreased MerTK RNA levels expression. MerTK expression was also downregulated by knockdown of Sp1, Sp3, or Sp4 and by treatment with mithramycin. Subsequent studies using chromatin immunoprecipitation and transfection of a MERTK (promoter)\u2013luciferase construct containing transcriptionally active GC-rich promoter elements indicated that MerTK expression in colon cancer cells was regulated by NR4A\/Sp complexes, including NR4A1, NR4A2, Sp1, Sp3, and Sp4 transcription factors. Conclusions: The participation of NR4A1 and NR4A2 in the regulation of MerTK indicates that DIM-3,5 ligands represent a novel class of agents that can be used to inhibit MerTK expression in cancer cells by acting as dual NR4A1 and NR4A2 inverse agonists.<\/jats:p>","DOI":"10.3390\/cancers18121993","type":"journal-article","created":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T09:18:43Z","timestamp":1781860723000},"page":"1993","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MerTK Is Regulated by Orphan Nuclear Receptor 4A1 (NR4A1) and NR4A2 in Colon Cancer Cells"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4278-7019","authenticated-orcid":false,"given":"Gargi","family":"Sivaram","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5236-3485","authenticated-orcid":false,"given":"Srijana","family":"Upadhyay","sequence":"additional","affiliation":[{"name":"Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3446-4851","authenticated-orcid":false,"given":"Sarah","family":"Kakwan","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0440-2739","authenticated-orcid":false,"given":"Ahmed","family":"Uosef","sequence":"additional","affiliation":[{"name":"Transplant Immunology, The Houston Methodist Research Institute, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maen","family":"Abdelrahim","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Houston Methodist Neal Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2228-457X","authenticated-orcid":false,"given":"Arafat Rahman","family":"Oany","sequence":"additional","affiliation":[{"name":"Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2724-5667","authenticated-orcid":false,"given":"Evan","family":"Farkas","sequence":"additional","affiliation":[{"name":"Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2115-3060","authenticated-orcid":false,"given":"Stephen","family":"Safe","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA"},{"name":"Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"5275","DOI":"10.1158\/1078-0432.CCR-12-1451","article-title":"Molecular Pathways: MERTK Signaling in Cancer","volume":"19","author":"Cummings","year":"2013","journal-title":"Clin. 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