The E3 ligase HECTD4 regulates COX-2-dependent tumor progression and metastasis
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (25)
Joanna A. Vuille
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Cem Tanriover
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Ezgi Antmen
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Douglas S. Micalizzi
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Richard Y. Ebright
Sambhavi Animesh
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Robert Morris
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Soroush Hajizadeh
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Zachary J. Nicholson
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Hunter C. Russell
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Eric F. Zaniewski
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Ben S. Wittner
Ben K. Wesley
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Ji Eun Kwak
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Julian Grunewald
Regan N. Szalay
Center for Computational and Integrative Biology, Massachusetts General Hospital
Douglas B. Fox
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Min Yang
J. Keith Joung
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Doga C. Gulhan
Andrew E. H. Elia
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Wilhelm Haas
Eugene Oh
Krantz Family Center for Cancer Research, Massachusetts General Hospital Cancer Center and Harvard Medical School
Shyamala Maheswaran
Daniel A. Haber