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

Autor:	Song K; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Cai X; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA., Dong Y; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Wu H; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Wei Y; Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA., Shankavaram UT; Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA., Cui K; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Lee Y; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Zhu B; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Bhattacharjee S; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Wang B; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Zhang K; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Wen A; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Wong S; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Yu L; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Xia L; Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA., Welm AL; Department of Oncological Sciences, University of Utah, Salt Lake City, Utah, USA., Bielenberg DR; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Camphausen KA; Radiation Oncology Branch, National Cancer Institute, Bethesda, Maryland, USA., Kang Y; Department of Molecular Biology, Princeton University, Princeton, New Jersey, USA.; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, New Jersey, USA., Chen H; Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2021 Jan 04; Vol. 131 (1).
DOI:	10.1172/JCI129374
Abstrakt:	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.
Databáze:	MEDLINE
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