A potential mechanism of ferroptosis modulation for immunotherapy in LUAD: ceRNAs networks of OTUD6B-AS1 modulate the balance of ubiquitination.

Abstract

e15111 Background: Ferroptosis plays a pivotal role in cancer progression and therapeutic response of immunotherapy in lung adenocarcinoma (LUAD). Recent studies on ferroptosis regulation by lncRNAs were conducted sporadically. Our study explored FrlncRNAs in LUAD comprehensively, exploring functional mechanisms and verified the correlation between ferroptosis and ubiquitination. Methods: Data of LUAD samples were download from GEO and TCGA databases. Annotated ferroptosis-related genes were retrieved from FerrDb and GeneCards databases. Ferroptosis-related lncRNA (FrlncRNAs) was identified by correlation analysis. The LASSO analysis and cox regression analysis were performed to filtrate significant prognostic FrlncRNAs, followed with model construction and patient stratification. Tumor immune microenvironment, functional pathways were investigated. Subcellular location and potential competing endogenous RNAs (ceRNAs) mechanisms were predicted by GDCRNATools algorithm. Results: Ferroptosis-related prognostic model constructed by 14 FrlncRNAs signature showed high prognostic efficacy with significant survival difference and robust area under the curve (AUC for 5 years survival: 0.89 in training cohort and 0.87 in validation cohort). Higher proportion of myeloid-derived suppressor cells were detected in high-risk group, of which ferroptotic status were supressed. Ferroptosis-enhanced samples harboured higher expression of immune checkpoints such as PD-L1, CTLA-4, TIM3 and CD47 and immune-recruiting interleukins such as IL2, IL4, IL7. Reasonably, more potential responders to immunotherapy were predicted in ferroptosis-enhanced samples. Considering the subcellular location, potential mechanism of ceRNA network was predicted that OTUD6B-AS1 may compete with mir-144 to regulate or modify NUDCD1 and MARCH7 through miRNA sponge. OTUD6B-AS1 encodes the protein of ovarian tumor domain deubiquitinase 6B, while MARCH7 contributes to a RING domain of membrane bound E3 ubiquitin ligases. GO, KEGG and GSEA pathway analyses focused on ubiquitin-protein transferase activity, polyubiquitination, mTOR, Hippo and NOTCH pathways. Protein-protein interaction identified hub genes in ferroptotic regulation such as NEDD8 and HERC2, which were coding genes of ubiquitin ligase E3 as well. Hence, the balance of ubiquitination and deubiquitination induced by the interplay of ceRNA network could be pivotal process in ferroptosis modulation in LUAD. Conclusions: In summary, we reveal potential mechanisms that OTUD6B-AS1 may compete with mir-144 to regulate the expression NUDCD1 and MARCH7 through miRNA sponge or modifying protein structures, modulating ferroptosis by balance of ubiquitination and deubiquitination. Ferroptosis may participate in the recruitment of immune system and portrait of tumor immune microenvironment.