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Cytoplasmic Miz1 Suppresses TNF-α-Induced NF-κB Activation and Hepatocellular Carcinoma Progression via the Interaction with Metadherin

ABSTRACT: Cytoplasmic Miz1 Suppresses TNF-α-Induced NF-κB Activation and Hepatocellular Carcinoma Progression via the Interaction with Metadherin

PROVIDER: PRJNA414205 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR6169220_1.fastq.gz	Fastqsanger.gz
	SRR6169220_2.fastq.gz	Fastqsanger.gz
	SRR6169221_1.fastq.gz	Fastqsanger.gz
	SRR6169221_2.fastq.gz	Fastqsanger.gz
	SRR6169222_1.fastq.gz	Fastqsanger.gz

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Project description:Background: Cancer immunotherapeutic strategies showed unprecedented results in the clinic. However, many patients do not respond to immuno-oncological treatments due to the occurrence of a plethora of immunological obstacles, including tumor intrinsic mechanisms of resistance to cytotoxic T cell attack. Thus, a deeper understanding of these mechanisms is needed to develop successful immunotherapies. Methods: To identify novel genes that protect tumor cells from effective T cell-mediated cytotoxicity, we performed a genetic screening in pancreatic cancer cells challenged with TILs and antigen-specific T cells. Results: The screening revealed 108 potential genes that protected tumor cells from T cell attack. Among them, salt-inducible kinase 3 (SIK3) was one of the strongest hits identified in the screening. Both genetic and pharmacological inhibition of SIK3 in tumor cells dramatically increased T cell-mediated cytotoxicity in several in vitro co-culture models, using different sources of tumor and T cells. Consistently, adoptive T cell transfer of TILs led to tumor growth inhibition of SIK3 depleted cancer cells in vivo. Mechanistic analysis revealed that SIK3 rendered tumor cells susceptible to TNF secreted by tumor-activated T cells. SIK3 promoted NF-ΚB nuclear translocation and inhibited Caspase-8 and -9 after TNF stimulation. Chromatin accessibility and transcriptome analyses showed that SIK3 knockdown profoundly impaired the expression of pro-survival genes under the TNF-NF-ΚB axis. TNF stimulation led to SIK3-dependent phosphorylation of the NF-κB upstream regulators inhibitory-κB kinase (IKK) and NF-kappa-B inhibitor alpha (IκBα) on the one side, and to inhibition of histone deacetylase 4 (HDAC4) on the other side, thus sustaining NF-κB activation and nuclear stabilization. A SIK3 dependent gene signature of TNF-mediated NF-κB activation was found in a majority of pancreatic cancers where it correlated with increased cytotoxic T cell activity and poor prognosis.

Dataset Information

Cytoplasmic Miz1 Suppresses TNF-α-Induced NF-κB Activation and Hepatocellular Carcinoma Progression via the Interaction with Metadherin

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