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The NF-ĸB p50 subunit generated by KPC1-mediated ubiquitination and limited proteasomal processing, suppresses tumor
Yelena Kravtsova-Ivantsiv1, Gilad Goldhirsh2, Ciprian Tomuleasa3
1The Rappaport Faculty of Medicine and Research Institute and the Rappaport Technion Integrated Cancer Center (R-TICC), Technion-Israel Institute of Technology, P.O. Box 9649, 3109601, Haifa, Israel. yelenaiv@technion.ac.il.
Abstract:
Nuclear factor-ĸB (NF-ĸB) is an important transcriptional regulator of key cellular processes, including cell cycle, immune response, and malignant transformation. We found that the ubiquitin ligase Kip1 ubiquitination-promoting complex subunit 1 (KPC1; also known as Ring finger protein 123 - RNF123) stimulates ubiquitination and limited proteasomal processing of the p105 NF-ĸB precursor to generate p50, the active subunit of the heterodimeric transcription factor. KPC1 binds to the ankyrin repeats' (AR) domain of NF-ĸB p105 via a short binding site of 7 amino acids-968-WILVRLW-974. Though mature NF-ĸB is overexpressed and constitutively active in different tumors, we found that overexpression of the p50 subunit, exerts a strong tumor suppressive effect. Furthermore, excess of KPC1 that stimulates generation of p50 from the p105 precursor, also results in a similar effect. Analysis of transcripts of glioblastoma and breast tumors revealed that excess of p50 stimulates expression of many NF-ĸB-regulated tumor suppressive genes. Using human xenograft tumor models in different immune compromised mice, we demonstrated that the immune system plays a significant role in the tumor suppressive activity of p50:p50 homodimer stimulating the expression of the pro-inflammatory cytokines CCL3, CCL4, and CCL5 in both cultured cells and in the xenografts. Expression of these cytokines leads to recruitment of macrophages and NK cells, which restrict tumor growth. Finally, p50 inhibits the expression of the programmed cell death-ligand 1 (PDL1), establishing an additional level of a strong tumor suppressive response mediated by the immune system.
Insights
The ubiquitin ligase KPC1 promotes the generation of the NF-κB p50 subunit, which exhibits potent tumor suppressive effects by enhancing immune responses and downregulating PD-L1.
Area of Science:
- Molecular Biology
- Immunology
- Oncology
Background:
- Nuclear factor-κB (NF-κB) is a key regulator in cellular processes like immune response and malignant transformation.
- The ubiquitin ligase KPC1 (RNF123) influences NF-κB pathway activity.
- Constitutive NF-κB activation is common in various cancers.
Purpose of the Study:
- To investigate the role of KPC1 in regulating NF-κB p50 generation.
- To determine the tumor suppressive potential of the NF-κB p50 subunit.
- To elucidate the mechanisms underlying p50-mediated tumor suppression, including immune system involvement.
Main Methods:
- Biochemical assays to study KPC1-mediated ubiquitination and processing of NF-κB p105.
- Transcriptomic analysis of glioblastoma and breast tumors.
- In vivo studies using human xenograft tumor models in immune-compromised mice.
Main Results:
- KPC1 directly binds to NF-κB p105 and promotes its processing to the active p50 subunit.
- Overexpression of p50 or KPC1 demonstrates significant tumor suppressive effects.
- p50 induces expression of pro-inflammatory cytokines (CCL3, CCL4, CCL5), recruiting immune cells to restrict tumor growth.
- p50 inhibits PD-L1 expression, further enhancing anti-tumor immunity.
Conclusions:
- KPC1-mediated generation of NF-κB p50 is a critical mechanism for tumor suppression.
- The tumor suppressive activity of p50 is significantly mediated by its ability to modulate the immune microenvironment.
- Targeting the KPC1-p50 axis offers a potential therapeutic strategy for cancer treatment.
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