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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,8,12]]},"abstract":"<jats:p>\n                    E3 ubiquitin ligases mediating turnover of proteins engaged in cancer progression point to key regulatory nodes. To uncover modifiers of metastatic competency, we conducted an in vivo genome-wide CRISPR-inactivation screen using cultured breast circulating tumor cells, following intravascular seeding and lung colonization. We identified HECTD4, a previously uncharacterized gene encoding a conserved potential homologous to E6AP C-terminus domain\u2013containing ubiquitin transferase, as a potent tumor and metastasis suppressor. We show that purified HECTD4 mediates ubiquitin conjugation in vitro, and proteomic studies combined with ubiquitin remnant profiling identify a major degradation target as the prostaglandin synthetic enzyme cyclooxygenase-2 (\n                    <jats:italic toggle=\"yes\">COX-2<\/jats:italic>\n                    ;\n                    <jats:italic toggle=\"yes\">PTGS2<\/jats:italic>\n                    ). In addition to COX-2 itself, HECTD4 targets its regulatory kinase MKK7. In breast cancer models, HECTD4 expression is induced as cells lose adherence to the matrix, and its depletion massively increases COX-2 expression, enhancing anchorage-independent proliferation and tumorigenesis. Genetic or pharmacologic suppression of COX-2 reverses the protumorigenic and prometastatic phenotype of HECTD4-depleted cells. Thus, HECTD4 encodes an E3 ubiquitin ligase that downregulates COX-2 suppressing anchorage independence in epithelial cancer cells.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2425621122","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T18:48:00Z","timestamp":1777920480000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":4,"title":["The E3 ligase HECTD4 regulates COX-2-dependent tumor progression and metastasis"],"prefix":"10.1073","volume":"122","author":[{"given":"Joanna A.","family":"Vuille","sequence":"first","affiliation":[{"name":"Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School","place":["Charlestown"]},{"name":"Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne University","place":["Lausanne, 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