The E3 ligase HECTD4 regulates COX-2-dependent tumor progression and metastasis

• 成果类型: Article
• 署名作者: Vuille, Joanna A.; Tanriover, Cem; Antmen, Ezgi; Micalizzi, Douglas S.; Ebright, Richard Y.; Animesh, Sambhavi; Morris, Robert; Hajizadeh, Soroush; Nicholson, Zachary J.; Russell, Hunter C.; Zaniewski, Eric F.; Wittner, Ben S.; Wesley, Ben K.; Kwak, Ji Eun; Grunewald, Julian; Szalay, Regan N.; Fox, Douglas B.; Yang, Min; Joung, J. Keith; Gulhan, Doga C.; Elia, Andrew E. H.; Haas, Wilhelm; Oh, Eugene; Maheswaran, Shyamala; Haber, Daniel A.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; University of Lausanne; Centre Hospitalier Universitaire Vaudois (CHUV); Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Howard Hughes Medical Institute; Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13317
• DOI: 10.1073/pnas.2425621122
• 发表日期: 2025-08-12
• 关键词: colorectal-carcinoma; protein expression; cyclooxygenase-2; celecoxib; inhibition; prevention; proteomics; GROWTH; MODEL; RISK

摘要

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-containing 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 (COX-2; PTGS2). 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.