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Transcriptomic effect of LDOC1 and H2Bub1 in NSCLC

ABSTRACT: Despite declining incidence and improved survival rate, lung cancer therapeutic outcomes remain unsatisfactory and still is a leading cause of cancer death. Metastasis and treatment resistance hampers the survival of lung cancer patients. Lung adenocarcinoma (LUAD) is the main subtype of lung cancer. Our studies showed that LDOC1 strongly inhibits human LUAD A549 cells invasiveness and LDOC1 knockdown (KD) sensitized A549 cells to cisplatin. The mechanisms have not been fully elucidated.Coimmunoprecipitation-western blot and confocal microscopic analysis demonstrated the interaction between LDOC1 and the E3 ubiquitin ligase RNF40. RNF40 and its paralog RNF20 forms a heterodimer to monoubiquitylate histone H2B on lysine 120. H2B monoubiquitination (H2Bub1) is a prominent epigenetic mark involved in a variety of cellular processes mainly by regulating the transcription of specific gene sets. Our results showed that LDOC1 negatively regulates H2Bub1 in cell lines and specimens of LUAD. The regulatory mechanism may involve the proteasome degradation of H2B and nuclear translocation of RNF40 mediated by LDOC1. Microarray analysis revealed LDOC1 KD caused a global change in gene expression. SLC7A11, which encodes a cystine-glutamate antiporter, is a key component of ferroptosis epigenetically regulated by H2Bub1 and is significantly upregulated in LDOC1-deficient A549 cells, supporting that the increased H2Bub1 level is the cause of transcriptome reprogram triggered by LDOC1 KD. The IPA results and GEPIA database suggested nine genes upregulated by LDOC1 KD were lethal metastasis gene (LM) candidates with their high expression is associated with shorter overall survival of LUAD patients. Genes involved in inhibition of idiopathic pulmonary fibrosis signaling and upregulated in LDOC1 KD cells will be considered as cisplatin-responsive (CS) gene candidates regulated by LDOC1/H2Bub1 axis.We hypothesized that LDOC1 epigenetically affects tumor metastasis and chemotherapy efficacy of LUAD via regulation of H2Bub1. We aimed to meta-analysis the gene expression array data and chromatin immunoprecipitation (ChIP)-sequencing data to identify lethal-metastasis (LM) and cisplatin-responsive (CR) genes that regulated by LDOC1/H2Bub1 axis in LUAD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235829 | GEO | 2026/03/06

REPOSITORIES: GEO

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Project description:Gene body-associated monoubiquitination of H2B (H2Bub1) coupled with promoter-associated active histone modifications such as trimethylation H3 on lysine 4 (H3K4me3) and acetylation H3 on lysine 27 (H3K27ac) facilitate gene transcription. However, surprisingly, only a subset of genes is altered in their expression following knockdown of H2B ubiquitin-protein ligases RNF20 or RNF40 in human cells. In order to obtain a more complete genome- and transcriptome-wide understanding of the role of H2Bub1 in gene transcription, we generated tamoxifen-inducible Rnf40 knockout mouse embryonic fibroblasts (MEFs). Mapping of H2Bub1, H3K4me3, H3K27me3, and H3K27ac occupancy identified an “ascending” gene cluster including bivalent genes, which is occupied by low to moderate amounts of H2Bub1 and exhibits high variability in transcription. We provide evidence that the variation in expression is highly associated with the variations in H3K4me3, H3K27me3, and H3K27ac occupancy. Moreover, these variably marked “ascent” genes are selectively regulated in Rnf40-deficient MEFs. Consistent with previous studies, the effect of Rnf40 loss on the expression of genes within this cluster is also variable with some genes demonstrating increased while others decreased mRNA levels following Rnf40 deletion. Importantly, we identified the Ezh2 gene as an Rnf40/H2Bub1 target whose expression significantly decreased in Rnf40-deficient MEFs. Notably, we show that genes upregulated following Rnf40 deletion are enriched for H3K27me3, which is decreased following Rnf40 deletion, and these effects can be mimicked by treating with a small molecule EZH2 inhibitor. On the other hand, consistent with findings in many eukaryotic systems, genes whose expression decreases following Rnf40 deletion show an enrichment of H3K4me3 and decreased levels following deletion. Together, we provide mechanistic information by which Rnf40, presumably via H2Bub1, modulates gene expression via coordination of the active and repressive marks H3K4me3 and H3K27me3.

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Transcriptomic effect of LDOC1 and H2Bub1 in NSCLC

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