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标题：Excess of the NF-ĸB p50 subunit generated by the ubiquitin ligase KPC1 suppresses tumors via PD-L1– and chemokines-mediated mechanisms
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作者：Yelena Kravtsova-Ivantsiv ; Gilad Goldhirsh ; Alexandra Ivantsiv 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2020
卷号：117
期号：47
页码：29823-29831
DOI：10.1073/pnas.2019604117
出版社：The National Academy of Sciences of the United States of America
摘要：Nuclear factor–ĸB (NF-ĸB) transcription factor is a family of essential regulators of the immune response and cell proliferation and transformation. A typical factor is a heterodimer made of either p50 or p52, which are limited processing products of either p105 or p100, respectively, and a member of the Rel family of proteins, typically p65. The transcriptional program of NF-ĸB is tightly regulated by the composition of the dimers. In our previous work, we demonstrated that the ubiquitin ligase KPC1 is involved in ubiquitination and proteasomal processing of p105 to generate p50. Its overexpression and the resulting high level of p50 stimulates transcription of a broad array of tumor suppressors. Here we demonstrate that additional mechanisms are involved in the p50-mediated tumor-suppressive effect. p50 down-regulates expression of a major immune checkpoint inhibitor, the programmed cell death-ligand 1 (PD-L1), both in cells and in tumors. Importantly, the suppression is abrogated by overexpression of p65. This highlights the importance of the cellular quantities of the two different subunits of NF-ĸB which determine the composition of the dimer. While the putative p50 homodimer is tumor-suppressive, the “canonical” p50p65 heterodimer is oncogenic. We found that an additional mechanism is involved in the tumor-suppressive phenomenon: p50 up-regulates expression of the proinflammatory chemokines CCL3, CCL4, and CCL5, which in turn recruit into the tumors active natural killer (NK) cells and macrophages. Overall, p50 acts as a strong tumor suppressor via multiple mechanisms, including overexpression of tumor suppressors and modulation of the tumor microenvironment by recruiting active immune cells.
关键词：ubiquitin ligase KPC1 ; PD-L1 ; NF-ĸB p50 ; tumor suppression ; chemokines