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CD95/Fas suppresses NF-B activation through recruitment of KPC2 in a CD95L/FasL-independent mechanism

ABSTRACT: CD95 expression is preserved in triple-negative breast cancers (TNBCs) and CD95 loss in these cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK cells impairing tumor growth. Herein, we identify a novel interaction partner of CD95, Kip1 ubiquitination-promoting complex protein 2 (KPC2) using an unbiased proteomic approach. Independently of CD95L, CD95/KPC2 interaction contributes to the partial degradation of p105 (NFκB1) and the subsequent generation of p50 homodimers, which transcriptionally represses NF-κB-driven gene expression. Mechanistically, KPC2 interacts with the C-terminal region of CD95 and serves as an adaptor to recruit RelA (p65) and KPC1, which acts as E3 ubiquitin-protein ligase promoting the degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines, that could account for the immune landscape remodeling in TNBC cells

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell

DISEASE(S): Breast Cancer

SUBMITTER: Luc Negroni

LAB HEAD: Patrick Legembre

PROVIDER: PXD027196 | Pride | 2021-12-06

REPOSITORIES: Pride

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			Action	DRS
	171128_PL_band01_rep1.msf	Msf
	171128_PL_band01_rep1.raw	Raw
	171128_PL_band01_rep2.msf	Msf
	171128_PL_band01_rep2.raw	Raw
	171128_PL_band01_rep3.msf	Msf

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CD95 expression in triple negative breast cancer blocks induction of an inflammatory state through differential regulation of NF-κB Signaling [MDA-MB-231]

Project description:CD95L is expressed by tumor-infiltrating lymphocytes to eliminate CD95-expressing tumor cells and thereby CD95 loss by tumor cells is often considered as a consequence of an immunoediting process. Nonetheless CD95 expression is maintained in most triple negative breast cancers (TNBCs), and we recently reported that CD95 loss in TNBC cells triggers the induction of a pro-inflammatory program promoting the recruitment of cytotoxic NK and CD8+ T-cells and impairing tumor growth. Using a comprehensive proteomic approach, we have identified two yet unknown CD95 interaction partners, Kip1 ubiquitination-promoting complex protein 2 (KPC2) and p65. KPC2 contributes to the partial degradation of p105 (NFκB1) and the subsequent generation of p50 homodimers, which transcriptionally represses pro-inflammatory NF-κB-driven gene expression. Mechanistically, KPC2 directly interacts with the C-terminal region of CD95 and links the receptor to RelA (p65) and KPC1, the catalytic subunit of the KPC complex that acts as E3 ubiquitin-protein ligase promoting the partial degradation of p105 into p50. Loss of CD95 in TNBC cells releases KPC2, limiting the formation of the NF-κB inhibitory homodimer complex (p50/p50), promoting NF-κB activation and the production of pro-inflammatory cytokines including CSF1, CSF2, CXCL1 and IL1 members, known to promote recruitment and differentiation of certain adaptive and innate immune effector cells.

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CD95 expression in triple negative breast cancer blocks induction of an inflammatory state through differential regulation of NF-κB Signaling [4T1]

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Multi-species RELA ChIP-seq of mammalian aortic endothelial cells before and after TNFα stimulation

Project description:TNFα has an evolutionary conserved role in mediating inflammation via activation of the transcription factor NF-κB. The functions of individual NF-κB binding sites are not well understood. To identify conserved and functionally important NF-κB binding sites in mammals, we performed ChIP-seq to map the genome-wide binding of RELA and select histone modifications in primary vascular endothelial cells (ECs) isolated from the aortas of human (HAEC), mouse (MAEC) and cow (BAEC), before and after TNFα. The conserved RELA binding sites show strong epigenetic changes in response to TNFα and enrich near genes controlling vascular development and pro-inflammatory responses. Our method identifies novel modes of RELA-chromatin interactions that are conserved in mammals and shared between multiple cell-types. Particularly, genomic regions bound by RELA prior to stimulation are important responders during TNFα stimulation. We use CRISPR/Cas9 genome editing to validate the roles of the conserved RELA pre-bound sites near pro-inflammatory genes such as CCL2 and PLK2. Our evolutionary approach describes new aspects of mammalian NF-κB biology including its role within super-enhancers and relevance in inflammatory disorders.

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Project description:Background: The most aggressive subtype of breast cancer, triple-negative breast cancer (TNBC), has a worse prognosis and a higher probability of relapse since there is a narrow range of treatment options. Identifying and testing potential therapeutic targets for the treatment of TNBC is of high priority. Methods: Using a transcriptional signature of triple-negative breast cancer collected from Gene Expression Omnibus (GEO), CMap was utilized to reposition compounds for the treatment of TNBC. CCK8 and colony formation experiments were performed to detect the effect of the candidate drug on the proliferation of TNBC cells, while flow cytometry was used to detect cell apoptosis. Meanwhile, transwell assay was implemented to detect cell metastasis change caused by the candidate drug. Moreover, the proteomic approach was presently ongoing to evaluate the underlying mechanism of the candidate drug in TNBC. Furthermore, drug affinity responsive target stability (DARTS) coupled with LC-MS/MS was carried out to explore the potential drug target candidate in TNBC cells. Results: We found that the most widely used medication, eugenol, reduced the growth and metastasis of TNBC cells. According to the underlying mechanism revealed by proteomics, eugenol could inhibit TNBC cell proliferation via the NOD1-NF-κB signaling pathway. DARTS experiment further revealed that eugenol may bind to NF-κB in TNBC cells. Concludes: Our findings pointed out that eugenol was a potential candidate drug for the treatment of TNBC.

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Project description:EZH2 has been studied most extensively in the context of PRC2-dependent gene repression. Paradoxically, accumulating evidence indicates non-canonical functions for EZH2 in cancer contexts including promoting gene expression in triple negative breast cancer (TNBC) cells through interactions with the transcription factor NF-kB. We define a genomic profile of EZH2 and NF-kB factor RelA, RelB, and NFKB2/p52 co-localization and positive regulation of a subset of NF-kB targets and genes associated with oncogenic functions in TNBC, which is enriched in patient datasets. We demonstrate interaction between EZH2 and RelA requiring the recently identified EZH2 transactivation domain (TAD), which mediates EZH2 recruitment to and activation of certain NF-kB-dependent genes, and supports downstream stemness phenotypes in TNBC cells. Interestingly, EZH2-NF-kB positive regulation of genes and stemness does not require PRC2. This study provides new insight into pro-oncogenic regulatory functions for EZH2 in breast cancer through PRC2-independent, and NF-kB-dependent regulatory mechanisms.

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