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

Abstract

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.

• Authors: Kai Song, Xiaofeng Cai, Yunzhou Dong, Hao Wu, Yong Wei, Uma T Shankavaram, Kui Cui, Yang Lee, Bo Zhu, Sudarshan Bhattacharjee, Beibei Wang, Kun Zhang, Aiyun Wen, Scott Wong, Lili Yu, Lijun Xia, Alana L Welm, Diane R Bielenberg, Kevin A Camphausen, Yibin Kang, Hong Chen
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 131 Issue 1 (01 04 2021) ISSN: 1558-8238 [Electronic] United States
• PMID: 32960814 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Adaptor Proteins, Vesicular Transport
• Epn2 protein, mouse
• Intracellular Signaling Peptides and Proteins
• NEMO protein, mouse
• Neoplasm Proteins
• epsin

Topics

• Adaptor Proteins, Vesicular Transport (genetics, metabolism)
• Animals
• Female
• Intracellular Signaling Peptides and Proteins (genetics, metabolism)
• Mammary Neoplasms, Animal (genetics, metabolism, pathology)
• Mice
• Mice, Knockout
• Neoplasm Proteins (genetics, metabolism)
• Signal Transduction
• Ubiquitination