Abstract 1490: Exon exclusion of NELF-E produces an anti-tumorigenic truncated isoform in hepatocellular carcinoma

Abstract

Abstract Overexpression of negative elongation factor E (NELF-E), a subunit of the negative elongation factor (NELF) complex involved in transcription pausing, has been implicated in poor hepatocellular carcinoma (HCC) outcome. We recently discovered an intronic heterozygous single nucleotide polymorphism (SNP), rs79208225 (G>A), near a spliceosome binding site in less than 1% of the general population but ~4% of our HCC cohort. HCC patients with the SNP had significantly longer times till recurrence (p=0.001) and better overall survival (p=0.02) compared to patients without the SNP. Using the minigene assay, we found the SNP causes exon 10 exclusion, which resulted in lower levels of full length NELF-E and the presence of a truncated NELF-E isoform that was not degraded via RNAi surveillance. We hypothesize NELF-E isoform switching is anti-tumorigenic in HCC. To investigate the effects of exon 10 exclusion, we employed antisense oligonucleotides (ASOs). HCC cells treated with ASOs had decreased cell proliferation and colony formation. Moreover, exon 10 exclusion enriched for the truncated NELF-E isoform and decreased full length mRNA and protein expression. Genetic models (CRISPR/cas9) showed similar phenotypes, suggesting that the truncated NELF-E is anti-tumorigenic. Currently, we are investigating the functional role of the truncated NELF-E protein in transcription regulation and the effects of isoform switching in HCC cells as a potential therapeutic strategy for HCCs with elevated NELF-E levels. Citation Format: Laura Reynolds, Ryan Lamm, Anna Barry, Meghan Grim, Kai Zhang, Hien Dang. Exon exclusion of NELF-E produces an anti-tumorigenic truncated isoform in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1490.