Epsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development.

TitleEpsins 1 and 2 promote NEMO linear ubiquitination via LUBAC to drive breast cancer development.
Publication TypeJournal Article
Year of Publication2021
AuthorsSong, 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
JournalJ Clin Invest
Volume131
Issue1
Date Published2021 Jan 04
ISSN1558-8238
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>

DOI10.1172/JCI129374
Alternate JournalJ Clin Invest
PubMed ID32960814
PubMed Central IDPMC7773373
Grant ListR01 HD083418 / HD / NICHD NIH HHS / United States
R01 HL146134 / HL / NHLBI NIH HHS / United States
R01 HL093242 / HL / NHLBI NIH HHS / United States
R01 DK085691 / DK / NIDDK NIH HHS / United States
R01 HL137229 / 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