Title | Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development. |
Publication Type | Journal Article |
Year of Publication | 2021 |
Authors | Song, K, Cai, X, Dong, Y, Wu, H, Wei, Y, Shankavaram, UT, Cui, K, Lee, Y, Zhu, B, Bhattacharjee, S, Wang, B, Zhang, K, Wen, A, Wong, S, Yu, L, Xia, L, Welm, AL, Bielenberg, DR, Camphausen, KA, Kang, Y, Chen, H |
Journal | J Clin Invest |
Volume | 131 |
Issue | 1 |
Date Published | 2021 Jan 04 |
ISSN | 1558-8238 |
Keywords | Adaptor Proteins, Vesicular Transport, Animals, Female, Intracellular Signaling Peptides and Proteins, Mammary Neoplasms, Animal, Mice, Mice, Knockout, Neoplasm Proteins, Signal Transduction, Ubiquitination |
Abstract | <p>Estrogen receptor-negative (ER-negative) breast cancer is thought to be more malignant and devastating than ER-positive breast cancer. ER-negative breast cancer exhibits elevated NF-κB activity, but how this abnormally high NF-κB activity is maintained is poorly understood. The importance of linear ubiquitination, which is generated by the linear ubiquitin chain assembly complex (LUBAC), is increasingly appreciated in NF-κB signaling, which regulates cell activation and death. Here, we showed that epsin proteins, a family of ubiquitin-binding endocytic adaptors, interacted with LUBAC via its ubiquitin-interacting motif and bound LUBAC's bona fide substrate NEMO via its N-terminal homolog (ENTH) domain. Furthermore, epsins promoted NF-κB essential modulator (NEMO) linear ubiquitination and served as scaffolds for recruiting other components of the IκB kinase (IKK) complex, resulting in the heightened IKK activation and sustained NF-κB signaling essential for the development of ER-negative breast cancer. Heightened epsin levels in ER-negative human breast cancer are associated with poor relapse-free survival. We showed that transgenic and pharmacological approaches eliminating epsins potently impeded breast cancer development in both spontaneous and patient-derived xenograft breast cancer mouse models. Our findings established the pivotal role epsins played in promoting breast cancer. Thus, targeting epsins may represent a strategy to restrain NF-κB signaling and provide an important perspective into ER-negative breast cancer treatment.</p> |
DOI | 10.1172/JCI129374 |
Alternate Journal | J Clin Invest |
PubMed ID | 32960814 |
PubMed Central ID | PMC7773373 |
Grant List | R01 HD083418 / HD / NICHD NIH HHS / United States R01 HL146134 / HL / NHLBI NIH HHS / United States R01 HL093242 / HL / NHLBI NIH HHS / United States R01 HL158097 / HL / NHLBI NIH HHS / United States R01 HL156362 / HL / NHLBI NIH HHS / United States R01 DK085691 / DK / NIDDK NIH HHS / United States R01 HL141853 / HL / NHLBI NIH HHS / United States R01 HL162367 / HL / NHLBI NIH HHS / United States P01 HL085607 / HL / NHLBI NIH HHS / United States R01 CA141062 / CA / NCI NIH HHS / United States R01 CA134519 / CA / NCI NIH HHS / United States R01 HL118676 / HL / NHLBI NIH HHS / United States R01 HL130845 / HL / NHLBI NIH HHS / United States T32 HL007917 / HL / NHLBI NIH HHS / United States R01 HL137229 / HL / NHLBI NIH HHS / United States |